COGNITIVE AND NEUROPSYCHOLOGICAL ASPECTS OF AGE-ASSOCIATED MEMORY DYSFUNCTION

A k a d e m is k a v h a n d l in g

som för avläggande av filosofie doktorsexamen med vederbörligt tillstånd av rektorsämbetet vid Umeå universitet framlägges för offentlig granskning vid Psykologiska institutionen, Umeå Universitet, Seminarierum 2, fredagen den 24 januari 1992, klockan 10.15

AV

Th o m a s K a r l s s o n

Psykologiska institutionen, Umeå Universitet, Umeå COGNITIVE AND NEUROPSYCHOLOGICAL ASPECTS OF AGE- ASSOCIATED MEMORY DYSFUNCTION

BY

Thom as K arlsson

Doctoral Dissertation Department of Psychology, University of Umeå, Umeå, Sweden

ABSTRACT

Memory dysfunction is common in association with the course of normal aging. Memory dysfunction is also obligatory in age-associated neurological disorders, such as Alzheimer’s disease. However, despite the ubiquitousness of age-related memory decline, several basic questions regarding this entity remain unanswered. The present investigation addressed two such questions: (1) Can individuals suffering from memory dysfunction due to aging and amnesia due to Alzheimer’s disease improve memory performance if contextual support is provided at the time of acquisition of to-be- remembered material or reproduction of to-be-remembered material? (2) Are memory deficits observed in ‘younger’ older adults similar to the deficits observed in ‘older’ elderly subjects, Alzheimer’s disease, and memory dysfunction in younger subjects? The outcome of this investigation suggests an affirmative answer to the first question. Given appropriate support at encoding and retrieval, even densely amnesic patients can improve their memory performance. As to the second question, a more complex pattern emerges. When attentional demands are varied, subjects of varying ages perform qualitatively similar. However, when semantic aspects of the to-be- remembered material are manipulated, age-associated qualitative differences are observed. These qualitative differences show up between older and younger adults, as well as between ‘younger’ and ‘older’ elderly subjects.

Key words: Aging, Alzheimer’s disease, Contextual support, Memory, Memory disorders

Author’s address: Department of Psychology, University of Umeå, S-901 87 Umeå, Sweden.

Umeå 1991; ISBN 91-7174-641-2 COGNITIVE AND NEUROPSYCHOLOGICAL ASPECTS OF AGE-ASSOCIATED MEMORY DYSFUNCTION

BY

T h o m a s K a r l s s o n 2 3

ABSTRACT

Memory dysfunction is common in association with the course of normal aging. Memory dysfunction is also obligatory in age-associated neurological disorders, such as Alzheimer’s disease. However, despite the ubiquitousness of age-related memory decline, several basic questions regarding this entity remain unanswered. The present investigation addressed two such questions: (1) Can individuals suffering from memory dysfunction due to aging and amnesia due to Alzheimer’s disease improve memory performance if contextual support is provided at the time of acquisition of to-be-remembered material or reproduction of to-be-remembered material? (2) Are memory deficits observed in ‘younger’ older adults similar to the deficits observed in ‘older’ elderly subjects, Alzheimer’s disease, and memory dysfunction in younger subjects? The outcome of this investigation suggests an affirmative answer to the first question. Given appropriate support at encoding and retrieval, even densely amnesic patients can improve their memory performance. As to the second question, a more complex pattern emerges. When attentional demands are varied, subjects of varying ages perform qualitatively similar. However, when semantic aspects of the to-be-remembered material are manipulated, age-associated qualitative differences are observed. These qualitative differences show up between older and younger adults, as well as between ‘younger’ and ‘older’ elderly subjects. 4

The dissertation is based upon the following papers:

I. Bäckman, L, & Karlsson, T. (1987). Effects of word fragment completion on free recall: A selective improvement of older adults.Comprehensive Gerontology, 7, 4-7.

II. Karlsson, T., Bäckman, L., Herlitz, A., Nilsson, L.-G., Winblad, B., & Österlind, P.-O. (1989). Memory improvement at different stages of Alzheimer's disease. Neuropsychologia, 27,737-742.

III. Karlsson, T., Adolfsson, R., Erstrand, B., Spiegel, R., Winblad, B., & Bucht, G. (1991). Somatostatin and glucose does not improve memory and cognition in Alzheimer’s disease. (Manuscript submitted for publication ).

IV. Bäckman, L., & Karlsson, T. (1986). Episodic remembering in young adults, 73-year-olds, and 82-year-olds. Scandinavian Journal of Psychology, 27, 320-325.

V. Nilsson, L-G., Bäckman, L., & Karlsson, T. (1989). Functionally similar memory deficits in old age, alcohol intoxication, and sleep deprivation. Psychological Medicine, 79, 423-433.

VI. Karlsson, T. (1990). Attention and memory in normal aging. (Manuscript submitted for publication). 5

ACKNOWLEDGMENT

My supervisor, Lars-Göran Nilsson, has not only provided financial backing during the initial stages of this project, but also been an excellent reviewer during the process of writing the individual papers, as well as the dissertation. In particular, though, Lars-Göran has been able to convey an interest in experimental psychology, which I did not anticipate when I started my graduate studies. I clearly acknowledge that this contribution can not be valued highly enough. In addition to Lars-Göran Nilsson, a number of persons have contributed to the investigations discussed in this dissertation, and I thank them all for their assistance. However, the contributions made, by Lars Bäckman and Rolf Adolfsson during various stages of this research clearly deserves special recognition. I also want to thank my wife, Katharina, for her support during the process of writing of this dissertation. 6

CONTENTS

Chapter One: Introduction...... 7 Prevalence of amnesia and memory dysfunction ...... 7 Etiologies of amnesia...... 8 The biochemical basis of memory...... 10 Mild to moderate memory dysfunction...... 12 Chapter Two: Experimental psychology of pure’ amnesia ...... 13 Experimental investigations of the amnesic syndrome...... 13 Theories about the amnesic syndrome...... 17 Summary ...... 25 Chapter Three: Age-associated memory dysfunction ...... 26 Theories of age-associated amnesia ...... 35 The neurobiology of normal aging and dementia...... 36 Chapter Four: Amnesia in neurodegenerative disorders and other conditions...... 43 Alzheimer’s disease ...... 43 Huntington’s disease...... 61 Cerebro-vascular disorders...... 63 Chapter Five: Summary of current investigation ...... 63 Experiment 1: Generation...... 67 Experiment 2: Memory improvement in Alzheimer’s disease...... 69 Experiment 3: Somatostatin treatment in Alzheimer’s disease ...... 71 Experiment 4: Encoding-retrieval interactions in old age...... 75 Experiment 5: Effects of priming and cued recall in elderly, sleep deprived and alcohol intoxicated subjects...... 79 Experiment 6: Working memory in old age...... 84 Discussion and conclusions...... 88 References...... 92 INTRODUCTION 7

CHAPTER ONE: INTRODUCTION

In recent years, the interest in memory dysfunction has increased steadily. Partly, this interest is due to the awareness that memory dysfunction is a common cognitive problem, particularly in adults. Partly, there is an interest in memory dysfunction because fundamental insights in human memory have been gained through the study of memory dysfunction. Despite this interest, and despite several important discoveries, many basic questions still remain unanswered. In particular, the cognitive mechanisms that are damaged in amnesia remain to be understood. Similarly, the manner in which memories are represented, is still unknown. Obviously, these questions are vital, not only for students of amnesia, but also for students of memory in normal individuals. Briefly, the dissertation comprises two parts. The first part (chapters one to four) contains a general discussion about memory dysfunction. The second section (chapter tive), presents six empirical investigations addressing topics related to memory dysfunction and, in particular, age associated memory dysfunction. The present chapter outlines the background; i.e., how often and when memory dysfunction and amnesia occur. The ensuing chapters deal with amnesia; age related memory decline; and memory dysfunction in dementia; respectively.

PREVALENCE OF AMNESIA AND MEMORY DYSFUNCTION

Although most researchers probably agree that memory problems are common, little is known about the exact prevalence and incidence of memory disorders. In particular, this holds true for milder, less dramatic alterations of memory functions. This because of several methodological difficulties related to epidemiological methods needed for determining prevalence and incidence. A recent British investigation (O’Connor, Pollitt, Roth, Brook, & Reiss, 1990) addressed the relationship between memory function and memory complaint in the elderly. Several such studies have of course been conducted before. However, one unique aspect of the study by O’Connor et al., was that it was based upon a large community survey of elderly persons. The investigation involved persons 75 years and older, who were to visit selected physicians in Cambridge, UK. The investigation involved two phases. In a first phase, subjects were tested by means of a brief neuropsychological battery, the Mini-Mental State examination (Folstein, Folstein, & McHugh, 1975). In a second phase, subjects were investigated more extensively, using the CAMDEX battery (Roth, Tym, Mountjoy, Huppert, Hendrie, Verma, & Goddard, 1986). The CAMDEX battery includes a sample of conventional memory tasks. The second phase included a total of 532 subjects. This phase incorporated persons who obtained scores of 23 and below on the Mini-Mental State examination and “a one-in-three sample of those subjects scoring 24 or 25” (p. 224). Of these subjects, 235 (or 44.17%) displayed symptoms of dementia, and, thus, memory dysfunction. Now, these subjects were initially selected from a larger sample, consisting of 2616 persons. Consequently, in a population 75 years and older, 8.98% could be expected to suffer from relatively clear-cut memory dysfunction. The finding of about 10% of the elderly suffering from marked memory dysfunction, is well in keeping with the results from ongoing studies by Reisberg and associates in the US and Nilsson, Winblad, Adolfsson, Bucht, and Bäckman in Sweden Nilsson, 1991; personal communication). However, it should be emphasized that these two investigations tell nothing about milder memory dysfunction taking place in the elderly, and nothing about memory dysfunction in younger adults. Such data are lacking, and it appears unlikely that these questions will be answered soon. 8 INTRODUCTION

Finally, it should be emphasized that the lack of epidemiological data is not at all unique to the field of memory research. On the contrary; little is known about neuropsychological problems in general. Regarding memory dysfunction, this applies to milder neuropsychological deficits in particular.

ETIOLOGIES OF AMNESIA

While memory dysfunction in general and the amnesic syndrome in particular are surrounded by numerous questions, there is one area that is understood in some detail. Several environmental factors and neurological conditions that lead to amnesia are known. Thus, amnesia can occur following surgical removal of limbic structures, as in case H. M. (Corkin, 1965, 1968; Corkin, Cohen, Sullivan, Clegg, Rosen, & Ackerman, 1985; Drachman & Arbit, 1966; Meyer & Yates, 1955; Milner, 1959,1966,1967; Penfield & Milner, 1958; Scoville & Milner, 1957; Terzian & Dalle Ore, 1955; Walker, 1957); and of the dorsomedial nucleus of thalamus (Orchinik, 1960). At least under circumstances where the lesion is large (Baleydier & Mauquiere, 1980), surgical removal of the cingulate gyrus produces a transient amnesia (Baleydier & Mauquiere, 1980; Whitty & Lewin, 1960). Amnesia has also been described in association with traumatic lesions to the medial thalamus (Lehtonen, 1973; Squire & Moore, 1979; Teuber, Milner, & Vaughan, 1968). Amnesia can be seen as a rare consequence of cardiac bypass-surgery, as was true with patient R. B. (Zola-Morgan, Squire, & Amaral, 1986). Amnesia is a cardinal symptom of Korsakoff’s syndrome (Butters & Cermak, 1980; Mair, Warrington, & Weiskrantz, 1979; Malamud & Skillicom, 1956; Talland, 1965; Victor, Adams, & Collins, 1971). Korsakoff’s syndrome is due to a deficit as to vitamin Bi (thiamine). This deficit can be seen in association with long-standing alcoholism, and occasionally, about extreme malnutrition, which, consequently, can produce amnesia (Victor, Adams, & Collins, 1971). Amnesia can be seen following encephalitis. Although several agents can cause encephalitis, amnesia has been repeatedly seen after herpes simplex type I infections, and following infection caused by Toxoplasma gondi (Brion & Mikol, 1978; Cermak, 1976; Cermak & O’Connor, 1983; Drachman & Adams, 1962; Hierons, Janota, & Corsellis, 1978; Rose & Symonds, 1960). For reasons that remain obscure, these agents apparently have a predilection for structures within the temporal cortex and the limbic system. Amnesia can also be the result of cardiac disease and subsequent anoxia (Cummings, Tomiyasu, Read, & Benson, 1984; Finkelstein & Caronna, 1978). Several studies have described amnesia in connection with infarction causing thalamic lesions (e.g., Graff-Radford, Damasio, Yamada, Eslinger, & Damasio, 1985; Mills & Swanson, 1978; Speedie & Heilman, 1982; von Cramon, Hebei, & Schuri, 1985; Winocur, Oxbury, Agnetti, & Davis, 1984). Amnesia has been observed in connection with ischemia (Volpe & Hirst, 1983; Zola-Morgan, Squire, & Amaral, 1986) and following occlusion of the posterior cerebral artery (Benson, Marsden, & Meadows, 1974). Ruptured aneurysms are known to give rise to amnesia (Linquist & Norlen, 1966; Norlen & Olivercrona, 1952). Furthermore, amnesia has been observed in connection with tumors of the third ventricle (Williams & Pennybacker, 1954). Head trauma can produce amnesia (Brooks, 1983; Russel, 1971; Russel & Nathan, 1946), and is most likely a common cause to severe memory dysfunction. An even more common cause to severe memory dysfunction and amnesia, are the neurodegenerative disorders. Of these disorders, Alzheimer’s disease is a predominant cause to amnesia (e.g., Miller, 1977; Morris & Kopelman, 1986; Swihart & Pirozzolo, 1988). However, amnesia can also be seen in association with Pick’s disease and the adult hydrocephalus syndrome. Finally, under certain conditions, amnesia can take place in association with electroconvulsive shock therapy (ECT), which sometimes is used to treat depressive illness (e.g., Barbizet, 1970; Squire, 1981, 1982a; Squire, Slater, & Miller, 1981). INTRODUCTION 9

As can be seen, amnesia can be caused by a number of adverse conditions affecting the central nervous system. Do these different causes bear any relation to anatomical structures and biological mechanisms of the brain? The answer appears to be affirmative. Therefore, it is possible to group the various causes to amnesia into a few broad categories (Huppert & Piercy, 1978a, 1979; Lhermitte & Signoret, 1972; Squire, 1982a, 1987). There are two regions of the central nervous system that have been implicated in the amnesic syndrome (Squire, 1987). One region is the inferior part of the temporal lobe, and, in particular, the hippocampus. In addition to surgical extirpation, most demented patients, post-encephalitic patients, post-anoxic and post-ischemic patients with amnesia suffer neuronal damage to the hippocampus. Similarly, it is believed that ECT treatment temporarily affects the functional integrity of the hippocampus. The other region of the brain associated with amnesia is the thalamus, and in particular the dorsomedial nuclei of the thalamus (Squire, 1987). Infarcts can, under rare circumstances, damage the thalamus selectively. However, ‘thalamic amnesia’ has primarily been associated with the alcoholic Korsakoff’s syndrome (Victor, Adams, & Collins, 1971). Despite the findings of thalamic damage in some amnesic patients, there is still some uncertainty about the role of the thalamus in memory functions. The medial thalamus has not been associated with amnesia to the same degree as the hippocampus. In particular, patients suffering from Korsakoff’s disease have damage to other brain regions as well; most notably the mamillary bodies of the hypothalamus, the cerebellum, and the frontal cortex. The mamillary bodies and the frontal cortex have, at times, been connected with amnesia and other cognitive functions. It can not be ruled out that some of these lesions contribute to the deficits observed in patients suffering from Korsakoff’s disease. (It should be noted, though, that lesions of the mamillary bodies produce no or only mild deficits in animal studies — see, e.g., Mishkin, Malamut, and Bachevalier, 1984.) While damage to the thalamus and (in particular) the hippocampus is associated with amnesia, less is known about how neocortical lesions are related to human amnesia. Some authors have described a correlation between cortical lesions and memory dysfunction (e.g., Luria, 1980); and it is possible that cortical lesions can produce memory problems. However, such memory problems probably differ from what is observed in the amnesic syndrome. First, unilateral lesions result in modality specific memory dysfunction (e.g., Kolb & Whishaw, 1985). The amnesic syndrome is usually not modality dependent (Hirst, 1982; Squire, 1982a; 1987). Second, lesions confined to cortical regions of the brain are not known to yield memory dysfunction of the depth and severity as observed in the amnesic syndrome. Third, it matters which cortical areas it is that are damaged. Fourth, cortical lesions commonly results in cognitive handicaps which by themselves interfere with memory functioning. Fortunately, it is possible to explain this pattern in a more simple way; without assigning a direct function to cortical structures in amnesia. It might well be that there is a relatively weak association between cortical damage and amnesia, because many cortical areas are anatomically connected to the hippocampus and the dorsomedial thalamus. More specifically, the hippocampus and the inferior temporal lobe receive afferent as well as efferent connections from the association areas of the neocortex (Mesulam, 1985; van Hoesen, 1982). Similarly, the medial nuclei of the thalamus are anatomically connected to inferior temporal lobe structures and to regions in the frontal cortex (Mesulam, 1985; Mishkin, 1982; Mishkin, Malamut, & Bachevalier, 1984). Thus, memory dysfunction due to neocortical damage might come about since some cortical regions work in parallel with the parts of the central nervous system that are critical to the integrity of memory. It should be emphasized that this hypothesis regarding the anatomical contribution of neocortical structures to memory functioning still remains a hypothesis. However, it might hold important implications for theories regarding memory, since many such theories often make the assumption that memory is distributed. Furthermore, one could ask if milder memory deficits (such as deficits seen in the elderly or due to acute alcohol intoxication) are due to disturbances with 10 INTRODUCTION respect to cortical function. Moreover, the hypothesis would give a neuropsychological account of the contribution that perception, understanding and attention makes to remembering. While it is possible to group the amnesias into two categories according to the localization of the lesion, it remains uncertain that there are two corresponding amnesia syndromes. It has been suggested (Huppert & Piercy, 1978a, 1979; Lhermitte & Signoret, 1972; Squire, 1982a) that amnesia associated with hippocampal lesions is characterized by accentuated forgetting, while amnesia associated with thalamic lesions would be due to some other deficit. It would certainly be important to disentangle two distinct amnesia syndromes. However, a more recent attempt directed at testing this hypothesis, failed to disclose accentuated forgetting in subjects with hippocampal amnesia (Freed, Corkin, & Cohen, 1987).

THE BIOCHEMICAL BASIS OF MEMORY

In recent years, a growing body of knowledge has been gathered regarding the role of neurotransmission and specific neurotransmitters in various aspects of mental life. The two most important fields in this respect are probably investigations of psychiatric disorders and memory and learning. Nowadays, it is common knowledge that the neurons of the central nervous system employ a vast number of chemical compounds to alter the state of other cells within the brain. Many of these substances are not unique to the brain, but can be found at other sites as well: in the peripheral nervous system and in the blood-stream. Since there is no generally accepted way of classifying such messengers, one common method is to classify them according to proven pharmacological proprieties. Some messengers have definitely been shown to act as neurotransmitters. Other messengers can, on good grounds, be expected to act as neurotransmitters; but the evidence is still inconclusive. Still other compounds appear to play an important role in the brain; however, the exact nature of their workings is still unclear. The first type of substances is sometimes referred to as the ”classical” neurotransmitters. These include the monoamines, serotonin, and acetylcholine. The monoamines can further be subdivided into adrenaline, dopamine, and noradrenaline. The second type of compounds includes substances such as glutamate, aspartate, histamine and GABA. Several of these substances are, by far, the most abundant molecules found in the central nervous system. Chemically, these substances are often smaller and simpler than other putative neurotransmitters. The final class of substances amounts to many of the neuropeptides. These are relatively large protein molecules, which can be found at many locations outside the nervous system where they have sometimes well delineated physiological effects. In addition to the more ”conventional” neurotransmitters, relatively little is understood about the biochemical underpinnings of memory. It seems possible that certain intracellular, second messengers can influence the cells’ internal expression of genes. Theoretically, such events can be important to structural changes underlying maturation and long-term aspects of memory and learning. Second, many enzymes are important to the functioning and integrity of the biochemical systems of the mind. As will be detailed later, the enzyme acetylcholinesterase is decreased in several neurodegenerative disorders (e.g., Rasmussen, Adolfsson, & Karlsson, 1988). Similarly, acetyl coenzyme A might be critically involved in the protection of neural tissue. However, the relation between possible enzymatic variations and cognitive functioning has seldom been studied. INTRODUCTION 11

Th e Cl a s s ic a l N eurotransmitters

The possibility that monoamines are related to aspects of learning and remembering receive support from neuropsychological investigations. Noradrenergic deficits appear to be quite common. They are typically found in neurological and neuropsychiatrie disorders, where memory deficits are abundant, if not obligatory. The conditions indicative of noradrenergic dysfunction amounts to Alzheimer’s disease (see, e.g., Gottfries, 1985), Korsakoff’s disease (McEntee & Mair, 1980) and depression (see, e.g., Siever & Davis, 1985). Despite these findings, the direct link between noradrenaline, dopamine and functions related to memory and learning remains unclear. It is possible that monoamines are more directly related to attention and attentional skills. Since about 1980, there has been a growing interest in the possibility that memory deficits might be linked to deficits with respect to the central cholinergic system. This interest was spurred by two findings. First, Drachman and Leavitt ( 1974) demonstrated that administration of the cholinergic antagonist scopolamine possessed amnesic properties. Healthy volunteers given scopolamine evidenced difficulties in conventional psychometric tasks tapping memory, but showed no deficits on other cognitive tasks. This amnesic effect was reversed by administration of physostigmine, but not by administration of amphetamine. Physostigmine has a marked effect at cholinergic sites by inhibiting the enzyme acetylcholinesterase, which in turn degrades acetylcholine. Amphetamine is thought to affect dopaminergic and/or serotoninergic neurotransmission. The second finding promoting the interest in the central cholinergic systems, was intimately linked to studies of patients suffering from Alzheimer’s disease. In 1981, Rossor suggested that the dementia characterizing Alzheimer’s disease was due to a central cholinergic deficit (Rossor, 1981; see also Coyle, Price, & Delong, 1983). Around that time, it was being made clear that patients suffering from Alzheimer’s consistently displayed reductions with respect to the enzyme choline acetyl transferase. (Choline acetyl transferase is involved in the synthesis of acetylcholine.) This enzymatic defect was in turn thought of as reflecting severe damage to cholinergic neurons, most notably the cholinergic neurons of the nucleus Basalis of Meynert. Since amnesia usually is regarded as a core symptom of dementia, the findings related to investigations of patients suffering from Alzheimer’s disease suggested that amnesia might be directly linked to damage to central cholinergic systems. During the ten years that have passed since the findings of reductions with respect to choline acetyltransferase, several attempts have been made to establish links between cholinergic abnormalities and specific clinical symptoms in Alzheimer’s disease. Regarding studies involving human subjects, these attempts fall into four distinct categories: (1) Correlations between post­ mortem markers for cholinergic neurotransmission and cognitive status prior to death; (2) Correlations between markers for cholinergic neurotransmission obtained in conjunction with brain biopsies and neuropsychological test performance; (3) Correlations between cerebrospinal fluid acetylcholinesterase and neuropsychological test performance; (4) Pharmacological trials, involving compounds aimed at improving or impairing cholinergic functioning. The outcome of studies that fall into any of the first three categories has, to this date, not lived up to the initial promises. Studies obtaining post-mortem levels of cholinergic markers, such as choline acetyltransferase, are difficult to conduct, not least due to logistic problems. In addition, patients dying from Alzheimer’s disease usually are in the terminal stage of the disorder. Therefore, reliable cognitive data might be extremely hard to obtain. Results from the second type of investigations — cholinergic markers obtained at biopsy — are rare. This is of course due to the ethical issues involved. Since effective treatment regimens are lacking, it is difficult to motivate the risks involved in obtaining biopsy material. At present, results 12 INTRODUCTION

of this kind (linking cholinergic markers from living Alzheimer patients to various aspects of cognitive performance) in a larger series of patients have been provided by David Bowen’s group in London. This work suggests a relation between cognitive function and various markers of the cholinergic system. Of the four points mentioned above, active pharmacological intervention is probably the tool that has generated the most promising results (for review, see Kopelman, 1986). However, it is still unclear to what extent cholinergic mechanisms are coupled to memory functions specifically. Cholinergic treatment influences not only performance in memory tasks, but also modifies performance in visuo-spatial tasks, as well as other intelligence measures. The converse holds true for compounds with anticholinergic properties: such drugs have effects beyond the effects on memory functions.

O th e r neurotransmuters a n d neuromodulators

Many other neurotransmitters and putative neurotransmitters have been implicated in functions related to memory. Today, glutamate and certain neuropeptides, such as somatostatin, receive special attention. These transmitters are depleted in patients evidencing cognitive impairment, and most notably patients suffering from Alzheimer’s disease. However, in contrast to acetylcholine, there has not been any efficient agonists available until recently. Consequently, experimental models as to these substances are still lacking.

MILD TO MODERATE MEMORY DYSFUNCTION

So far, the discussion has been concerned with the more severe forms of amnesia. Far less is known about the epidemiology and etiology of milder memory dysfunction. For instance, it is of course known that the course of normal aging is associated with memory dysfunction; however, it is not known how many older individuals who suffer from ‘age-associated memory impairment’ — AAMI (Crook, Bartus, Ferris, Whitehouse, Cohen, & Gershon, 1986). Similarly, risk factors for this putative clinical entity are not known, and it is not known if age-associated memory impairment itself constitutes a risk for further cognitive deterioration. A similar situation exists regarding most other causes to milder memory dysfunction. This author is not aware of any comprehensive summary or review regarding risk factors for mild and mild to moderate memory dysfunction. Until such a study has been undertaken, it is only possible to speculate about causes to memory dysfunction. Memory dysfunction can be associated with: (1) developmental changes, (2) neurological disorders, (3) psychiatric conditions, (4) drug use, (5) pharmacological treatment and intoxication, (6) industrial hygiene, (7) physical illness, (8) sports, (9) benign psychological conditions, (10) affective changes, (11) alterations as to the sleep-waking cycle, and (12) malnutrition. Concerning some of the points listed, an impressive body of knowledge already is at hand. This is true about memory functioning in infancy and old age, as well as memory dysfunction associated with neurological disorders. However, in most other cases, little is known. This is true, also with respect to risk factors that most likely are of paramount importance (e.g., item 12 above). Of the general types of memory disruptive events referred to above, most can be subdivided into further detail. For example, drug induced memory dysfunction can be grouped according to the particular drug involved (e.g., alcohol or marijuana). In some cases, these instances may not be strongly related. Thus, memory lapses due to fewer have, of course, little in common with memory dysfunction due to an endocrine disorder, such as hypothyreosis, or memory dysfunction following INTRODUCTION 13 stroke. Not only are the etiologies different; in addition, the prognosis varies. There is also some overlap between the categories in the scheme. Thus, carbon monoxide poisoning could be regarded as an ‘intoxication’, as well as a physical illness. Memory dysfunction due to neurodegenerative disorders and the course of normal aging, is discussed in some detail elsewhere in the dissertation. However, concerning most of the conditions listed above, very few (if any) experimental reports have been published. Consequently, it is not known whether qualitative differences between the various forms of memory dysfunction exist. It is possible that the delineation of memory dysfunction in the conditions listed above, will become an important task for students of memory in the years to come.

CHAPTER TWO: EXPERIMENTAL PSYCHOLOGY OF ‘PURE’ AMNESIA

One of the most fascinating areas of cognitive neuropsychology regards the investigation of human amnesia. In fact, the study of a few patients suffering from amnesia has contributed enormously to the understanding of human memory. Although this thesis is not about ‘pure’ amnesia, a discussion regarding ‘pure’ amnesia can not be avoided when other forms of memory impairment are discussed. This chapter will indicate important empirical findings as to the amnesic syndrome. In addition, theoretical explanations of amnesia are to be outlined.

EXPERIMENTAL INVESTIGATIONS OF THE AMNESIC SYNDROME

The summary regarding empirical findings in amnesia will include six topics: (a) performance in short- and long-term memory tasks; (b) studies on forgetting; (c) encoding processes; (d) retrieval processes; (e) encoding-retrieval interactions; and (0 implicit memory.

PERFORMANCE IN SHORT- AND LONG-TERM MEMORY TASKS

A defining characteristic of human amnesia is the dissociation between performance in short-term memory tasks and performance in long-term memory tasks. In general, most aspects of short-term memory functions are preserved in amnesia (e.g., Butters & Cermak, 1980; Wickelgren, 1968). A particularly strong case in favor of sparing of short-term memory functions, regards the description of patients displaying impaired short-term memory in the context of spared long-term memory (e.g., Baddeley & Wilson, 1985; De Renzi & Nichelii, 1975; Shallice & Warrington, 1974; Warrington & Shallice, 1969; 1972).

FORGETTING

If amnesia is not the consequence of a short-term memory or registration deficit, it is possible that amnesia is due to forgetting. However, surprisingly little evidence has been gathered in favour of this option. Actually, available evidence suggests that amnesic patients forget at a rate similar to controls. As an example, Freed, Corkin, and Cohen (1989) compared the recognition performance of the amnesic patient H. M. with the performance of controls at different time interval subsequent to study of pictures. When initial learning was equated in controls and the amnesic subject, H. M. did not differ from controls when recognition performance was tested at longer delays. Thus, H. M. does not forget at a faster rate than do controls - at least when encoding has been ascertained. 14 THE AMNESIC SYNDROME

ENCODING PROCESSES

An often proposed explanation to amnesia regards the possibility that amnesia is due to encoding deficits1. In particular as regard patients suffering from Korsakoff’s syndrome, there is evidence in favour of this hypothesis (e.g., Butters & Cermak, 1980; Cermak, 1989). However, it is also clear that patients with other amnesic syndromes than Korsakoff’s syndrome evidence normal effects of encoding support. Therefore, the encoding deficit reported by Butters, Cermak and colleagues, might be specific for Korsakoff patients.

RETRIEVAL PROCESSES

Just as investigators have proposed that amnesic patients suffer from encoding deficits, other theorists have proposed that amnesia is due to a retrieval deficit. It was once thought that cued recall procedures in general attenuated amnesia. However, it was soon realized that only certain cued recall procedures improved memory performance in amnesics. More specifically, those procedures that attenuated amnesia had an obvious implicit component. Therefore, these results are not considered to reflect a retrieval deficit in the strict sense of the term. A second problem with respect to retrieval explanations of amnesia, regards the fact that differences between amnesic patients and controls usually disappear, if the memories of controls are made ‘weak’ (Meudell & Mayes, 1984). Therefore, the differential effect of cueing at times observed in amnesia, could be due to initial differences as to intercept.

En c o d in g -r e t r ie v a l interactions

Many researchers have addressed questions related to encoding or retrieval in amnesia. However, accounts in terms of encoding-retrieval interactions are rare. This is remarkable, given the importance of the concept of encoding-retrieval interactions in the psychology of memory. However, recently Cermak and associates reported an encoding-retrieval experiment in Korsakoff amnesics (Cermak, Uhly, & Reale, 1980). Interestingly enough, the amnesic performed strikingly better when recall was guided by semantic cues at encoding and retrieval. However, when encoding and retrieval contexts were identical, amnesics were unable to recall the critical information. Typically, controls perform equally well in both conditions. It is likely that more encoding-retrieval experiments will be conducted in the future. It is possible to understand amnesia in terms of encoding-retrieval interactions; the amnesic patient might be unable to combine the results of encoding with retrieval information, unless there is a very strong overlap between trace and cue.

PRIMING AND IMPLICIT MEMORY

One of the most important findings as regard amnesia, concerns the finding of spared priming and intact performance in implicit (or indirect) memory tasks in amnesia. Some amnesic patients are able to reproduce elements of an earlier encounter, if no explicit reference to an earlier study episode is made. Typically, amnesics reproduce memorized words when presented word stems (Graf & Schacter, 1985), picture fragments (Warrington & Weiskrantz, 1968), or when asked to

lrThe term ‘encoding’ generally refers to the ability to aquire information in a manner such that it can reside in a permanent state. The term is often contrasted to ‘storage’ and ‘retrieval’; these terms denote ensuing stages in the processes of remembering. In recent years, researchers have come to emphasize the interaction between encoding and retrieval processes. That is, the influence upon memory by a certain encoding operation, partly depends upon how the particular episode is retrieved. THE AMNESIC SYNDROME 15

spell homophones (Jacoby & Witherspoon, 1982). Furthermore, amnesics evidence priming in the lexical decision task (Moscovitch, 1982b). In general, these findings suggest that amnesia is a relatively circumscribed disorder. Unfortunately, a more detailed explanation of this curious finding still remain elusive. The findings hold important practical implications. Amnesics perform normally in many implicit memory tasks. In theory, it follows that amnesics could be able to express their previously acquired knowledge if the conditions during testing are arranged in such a manner that the amnesic subjects do not have to remember the critical material in a conscious manner. For example, a person suffering from memory decline could be able to learn and perform a professional skill, although he really does not remember much of being, say, an electrician or a programmer! Actually, a smaller number of case studies and reports have described new learning of complex skills in amnesia. The first report probably dates as early as 1845. In this year, Dunn (1845) described a patient who could learn dressmaking, without direct awareness of having these professional skills. Similarly, Dana (1894) described an amnesic patient who could learn billiards and carving. In more recent times, Starr and Phillips (1970) reported of a patient who was able to learn how to play novel tunes on the piano. This learning occurred, although the patient could not remember having heard — or played — the very same melodies. Finally, Teuber, Milner and Vaughan (1968) reported that the patient N. A. learned how to build models after the onset of amnesia. Unfortunately, there are also indications suggesting that this method not always works. In particular, this appears to be the case with respect to those investigations which represents attempts at investigating “implicit learning” under controlled conditions. In a less often cited part of their work, Warrington and Weiskrantz (1978) engaged normal subjects and amnesic patients in completing three-letter word-fragments, following study of the very same words. The word-fragments used in this investigation were special, in the sense that they corresponded to only two unique English words. During the first phase of this experiment, the subjects studied a list of words. After the presentation, the subjects were given a number of word-fragments, and were asked to solve as many as possible. The word-fragments used in this phase of the investigation all corresponded to the words in the study list. As in previous investigations by these authors (Warrington & Weiskrantz, 1968; 1970; 1974; Weiskrantz & Warrington, 1970), amnesic patients performed at a level similar to controls in this indirect test of memory. For amnesics as well as for control subjects, the probability of solving the word-fragments was about .35. (The probability for responding without previous study was smaller than .10.) However, at four succeeding trials, the subjects were presented the alternate version of the two-solution fragments. In this phase of the experiment, amnesics were markedly impaired when asked to switch to an alternate response. The outcome of this experiment suggests that there exist some limitations to amnesic patients' abilities in indirect memory tasks. One limitation could be, that amnesics perform at an inferior level when the task demands of an indirect memory task require some type of mental flexibility or alteration of cognitive set. The patient H. M. is perhaps the case of human amnesia most intensively investigated thus far. In 1955, H. M. underwent neurosurgical extirpation of the hippocampus bilaterally. The operation was undertaken to cure an intractable epileptic disorder. Subsequent to the operation, H. M. became densely amnesic, and has remained so ever since. Several investigations have described that the patient H. M. is able to learn motor skills, perceptual skills and problem-solving skills (Cohen, 1984; Corkin, 1965; 1968). What about language skills? Obviously, the language is not unchanging. Every week, new words are added to our vocabulary. Can an amnesic patient modernize his vocabulary? 16 THE AMNESIC SYNDROME

Nyssen (1956) asked patients suffering from Korsakoff’s disease to define a set of words. Some of the words in Nyssen’s experiment were established since long; other words were contemporary. Korsakoff patients had no difficulties at explaining older words, but were deficient with respect to explaining the meaning of contemporary words. (In an interesting part of the study, Nyssen also asked patients to recall words drawn from the two categories. A clear advantage was obtained as to older words. This advantage was observed in Korsakoff’s disease patients as well as in controls.) More recently, Gabrieli, Cohen, and Corkin (1983) tried to learn H. M. eight novel words. These eight words were presented 115 times per day, for 10 days. Despite the ambitious scheme, H. M. showed practically no learning at all. This negative finding occurred, despite the fact that H. M. was not asked to remember the eight words explicitly. In fact the result of this experiment is a clear demonstration of a phenomenon that quite often is noted when an amnesic patient is engaged in conversation. These patients often use words and phrases being in vogue at the time when the amnesia was acquired. Cermak and O’Connor (1983) investigated the ability of the amnesic patient S. S. to use technological knowledge. The patient S. S. had acquired an amnesic syndrome following encephalitis. In addition, he was an authority in the field of laser technology prior to his illness. In an ingenious investigation, Cermak and O’Connor presented passages from scientific communications to S. S. Subsequent testing evidenced that S. S. had no problems with respect to (a) recall of knowledge acquired before his illness; and (b) the ability to comprehend and explain the contents of advanced passages of scientific prose. However, S. S. was incapable of remembering the very same prose passages, even at short retention intervals. This defect was evident irrespective of type of test (recall or recognition). In addition, S. S. did not evidence learning although numerous learning trials were administered. Glisky, Schacter and Tulving (1986) conducted an attempt at teaching four patients computer and programming skills. The task embodied different aspects of handling a computer: feeding information into the machine, saving data on discs, and writing short programs. The subjects in this study suffered from memory problems following head trauma. The subjects in the investigation conducted by Glisky, Schacter and Tulving did evidence learning of computer skills. However, this new learning was different from the learning in controls. First, there were quantitative differences. Healthy controls acquired the computer tasks at a much faster rate. Second, and most interestingly, the amnesic patients learned the tasks in what appears to have been a more shallow manner. They were to a very large degree dependent upon the reinstitution of the conditions surrounding acquisition of the computer task. For example, if the wording of a question was slightly changed from study to test, this made it very difficult for the memory impaired to come up with a correct answer. In this sense, Glisky et al. replicated the experimental finding by Warrington and Weiskrantz (1978), as described earlier on: Amnesia patients suffer in procedural or indirect memory tasks, if the specific task calls for some type of mental flexibility. Obviously, it would be of theoretical interest — and clinical utility — to know more about amnesic patients' putative deficiencies in this regard. For instance, it might be the case that the generalization of a specific cognitive skill thrives upon explicit remembering. In order for amnesic patients to evidence priming also in a broader context, other aspects of the task perhaps have to be possible to access by means of indirect procedures. It could also be that priming represents some kind of “fine tuning” of an already established response or sequence of responses. However, setting up new responses requires explicit knowledge. Finally, it might be that the amnesic syndrome consists of additional, and less well-know deficiencies. For instance, amnesic patients might suffer from deficits with respect to categorization of complex information. Be it however as it may be, little is known about these topics. The understanding of human amnesia could profit substantially from such knowledge. THE AMNESIC SYNDROME 17

The findings discussed in the previous paragraphs also present a theoretical problem to contemporary interpretations of performance in implicit memory tasks in amnesia. In some implicit memory or procedural learning tasks amnesics perform at normal or near-normal levels; in other tasks they do not. For example, individual amnesia patients evidence quite normal acquisition of the ”Tower of Hanoi” problem (Cohen, 1984); but not of the pursuit rotor task (Corkin, 1965; 1968; see also Cermak, Lewis, Butters, and Goodglass, 1973 ; Cermak and O’Connor, 1983).

THEORIES ABOUT THE AMNESIC SYNDROME

A large number and variety of theories have been invoked to explain the cognitive deficits seen in various forms of amnesia. The number of explanations proposed, makes it difficult to subsume the amnesic phenomena under a comprehensive body of theoretical explanations. For example, in the 1960s, Talland listed well more than 40 different theoretical accounts of the amnesic syndrome (Talland, 1965). Since then, the number of theoretical explanations probably has not been reduced. Therefore, given the multitude of theoretical accounts available, a metatheoretical outline is needed. Recently, Klatzky (1988) suggested a number of points, by means of which effects of aging upon cognitive performance could be understood. These points can easily be adapted to summarize theories of memory dysfunction, not only in the context of aging. Utilizing Klatzky’s classificatory scheme, amnesia can be understood in the following terms: 1. Amnesia might be the result of generalized systemic damage. Typical examples of this hypothesis are the interpretation of age-associated memory decline in terms of reduced processing speed, or the explanation of amnesia in terms of defective field structure. (These ideas are explained later on.) 2. A second type of explanation regards amnesia as the product of damage to a major system component. A typical example in this regard is explanations in terms of working memory deficits. 3. A third kind of explanation or theory regards selective effects on data structures in long-term memory. The most common example in this regard, is the hypothesis meaning that declarative knowledge is selectively affected in amnesia. 4. Effects on major processing mechanisms (e.g., on-line, deep processing). The basic idea here, is that amnesia is due to the dysfunction of a crucial stage or type of processing. The most common explanation in this regard is the interpretation of amnesia in terms of levels of processing. 5. A fifth, major type of theoretical account of amnesia, is the interpretation of amnesia in terms ofselective effects on subprocesses of remembering. Most theoretical accounts of amnesia somehow involve this type of account. Presumably the most common version of this type of explanation, highlights the temporal aspects of the process of remembering. That is, amnesia is understood in terms of deficits with respect to encoding, storage, consolidation, or retrieval of information. This approach is sometimes combined with explanations in terms of impaired processing mechanisms (such as the levels of processing approach) or explanations in terms of generalized systemic damage. 6. A final type of explanation regards interpretations of amnesia in terms of damage to selective subprocesses of mental functions, not specifically related to remembering. Although explanations of this kind are not as frequent as theories belonging to the aforementioned categories, they hold a place as one major type of account of amnesia. This is true, not the least since amnesic patients at time demonstrate marked proficiency with respect to remembering (see the discussion of implicit memory later in this chapter and in following chapters). At the same time, however, attempts towards ’unexplaining’ amnesia sometimes become devoid of content: any deficit seen in amnesia can be accounted for by mechanisms not well-suited for experimentation. Furthermore, although memory science can not explain amnesia, some other subdivision of the cognitive sciences must do 18 THE AMNESIC SYNDROME

so. Thus, the task of explaining amnesia is not so much accomplished as it is shuffled around between the subdivisions of cognitive science... Although these six types of conjectures all have been advocated to explain memory dysfunction, they are also connected to different periods of the history of psychology. Thus, unitary explanations, that is, explanations of amnesia in terms of damage to one single mechanism, or one specific general process, seem to be less frequent in contemporary theories (however, see Hirst, 1982, for an exception to this putative ‘rule’).

Am n e s ia a s a f u n c t io n o f generalized s y s t e m ic d a m a g e

Amnesia could be looked upon as the consequence of generalized systemic damage. Such views seem to have been present in older literature. Several of the most influential of the earlier theorists supported the view that amnesia was the product of large lesions to the brain. Also, it was believed that memory functions in no way at all were localized. Such positions were expressed by the gestalt psychologists (e.g., Koffka, 1935), and by Karl Lashley (1950). Although positions of this kind still can be found, empirical work subsequent to the proposals made by the pioneers of psychology seem to have made this position obsolete. One recent proposal, however, falls into this category. Hirst (1982) offered a hypothesis which assumes that amnesia emerges as a consequence of damage to a central system component. According to Hirst’s hypothesis, amnesics suffer from a deficit with respect to automatic processes. As a consequence, amnesics have to allocate effort to mental operations which normally are carried out in an automatic manner. In intact persons, the hypothesis continues, temporal and spatial aspects of events are, on the whole, encoded in an automatic way. Because these aspects also are crucial to performance in memory tasks, the deficit with respect to automatic processes produces amnesia. Just like any hypothesis implicating encoding deficits in amnesia, the hypothesis regarding deficits as to automatic processes suffer from difficulties when it comes to explaining why notall automatic processes are impaired in amnesia. That is, from the outset it appears that if anything is not affected in amnesia, it is automatic processes. Amnesic patients can read and derive meaning from text; amnesics react to novel and noxious stimuli, and so on. A second problem with the automatic processing hypothesis, is that it is just as possible to argue that amnesia might be brought about as a consequence of damage to effortfull processes. In fact several authors have suggested that various types of memory dysfunction could be explained in this manner: amnesics suffer from deficits as regards effortfull processes (Craik, 1977b; Hasher & Zacks, 1979).

A m n e s ia a s t h e o u t c o m e o f d a m a g e to a m a j o r s y s t e m c o m p o n e n t

From the outset, it might appear obvious that conceptualizations in terms of damage to one or several major system components should be among the most influential theoretical positions. However, this is not the case. There are most certainly several reasons to this state of affairs. First, the science of memory is a young science. Consequently, writers have not yet been able to delineate major system components of the human memory system. Second, the relatively few important contributions that have been made, have not directly touched upon phenomena such as amnesia. A typical example at hand is the working memory model of Baddeley (Baddeley, 1984). Although this model can account for memory dysfunction in Alzheimer’s disease, it is not primarily intended as an explanation of the amnesic syndrome. THE AMNESIC SYNDROME 19

AMNESIA AS A MANIFESTATION OF SELECTIVE DAMAGE TO DATA STRUCTURES IN LONG-TERM MEMORY

In recent years, the most common interpretation of deficits seen in amnesia, is probably the interpretation of amnesia in terms of damage to data structures in long-term memory. These conceptualizations thrive upon the distinction between declarative and procedural aspects of knowledge, or the distinction between episodic and semantic memory. The former distinction was originally introduced by Bergson (1910, cited in Squire, 1982) and Ryle (1949); its modem formulation has been provided by Squire and Cohen (1980). The distinction between episodic and semantic memory originates from Tulving (1983). Briefly, most conceptualizations of this kind assume that there are different memory systems, which fulfill different functions in the on-line process of remembering. Most theories of this kind assume that at least one such system is specialized in the management of explicit knowledge. Furthermore, in some of these models, it is assumed that the explicit knowledge regards autobiographical information, or is related to temporal and/or spatial features of the critical information. The most controversial, and at the same time, probably the most well-known proposition of this kind has been the distinction between episodic and semantic memory (Tulving, 1972, 1983). Originally, this hypothesis was a dichotomy of memory. Later on, the distinctions made have been developed, and additional complexity has been added to the proposal. It should also be underscored, that this distinction is not connected directly to amnesia research. Rather, the phenomenon of amnesia is one class of phenomena to which the proposal applies. According to the episodic-semantic memory distinction, stored knowledge must be of two types. A first class of knowledge involves general knowledge about the world. That is, factual knowledge, knowledge about words, language, and other forms of communication, social scenarios, and so forth. The second kind of knowledge regards autobiographical information. That is, where a particular event took place, when it was, who where there, and so on. According to Tulving, the main difference between these two systems stems from the fact that retrieval, reconstruction of stored information, is more restricted in the case of episodic memory. Episodic memory is concerned with the temporal and spatial features of events. Consequently, the rememberer needs to reconstruct this information in order to be able to come up with an answer. In the case of activation of information stored in semantic memory, temporal and spatial connotations are usually trivial. Otherfactors, such as speed, might be more important here, though. As to amnesia, it has been suggested that amnesia takes place due to a selective derangement of episodic memory (e.g., Parkin, 1982). Although this might seem plausible to some authors, most writers reject this notion on empirical grounds. It is simply not correct that amnesic patients have intact semantic memories. For instance, amnesic patients have never been demonstrated to acquire novel semantic information. Cermak and O’Connor’s subject S. S. is a case at hand (Cermak & O’Connor, 1983). A more frequent, and perhaps more fruitful solution, has been to suggest the existence of more than two memory systems. Tulving has suggested that intact priming (and other examples of intact learning and/or memory performance) is due to the preservation of a third memory system. In contrast to the episodic and semantic systems, this third system stores information in a much more fragmented form. In addition, the records of this system can be of long endurance. Finally, the contents of this system need not gain access to consciousness in order to produce a response. Recently, Tulving and Schacter (1990) have termed this system the perceptual representation system (PRS) (Tulving and Schacter, 1990). This system is thought to contain residual copies of the products of perceptual analysis. Since this system is not dependentupon structures that are critical to conscious recollection (such as the hippocampus), the workings of the PRS can be unaffected in some cases of amnesia. 20 THE AMNESIC SYNDROME

A second, major, formulation of amnesia in terms of damage to data structures, regards the distinction between declarative and procedural knowledge (Cohen & Squire, 1980; Squire, 1987). Declarative knowledge concerns facts that have to be specified in some regard: in relation to other facts, in relation to some temporal parameter, or according to a spatial rule. Thus, declarative knowledge amounts to knowledge about oneself, about other people, and about the world in general - in short, facts. In contrast, procedural knowledge amounts to knowledge about ‘how to’ do things, i.e., skills. According to some writers, then, amnesia comes from an inability to acquire declarative knowledge. Although these two, recently mentioned distinctions has received the widest attention as regards hypothesis emphasizing damage to data structures, it should be briefly indicated that several other theorists have offered similar distinctions. Using evidence from animal experiments, Olton proposed a distinction between reference memory and working memory (Olton, Becker, & Handelmann, 1979). O’Keefe and Nadel (1978) suggested a distinction between a taxon system and a locale system. The latter system was believed to contain information about the temporal orderings between events, and was suggested to be localized in the hippocampus. Which of the different versions of the hypothesis emphasizing damage to data structures, is most effective? There is no unambiguous answer to this question. However, several writers have pointed to the possibility that the distinctions offered by Tulving and Schacter on the one hand, and Cohen and Squire on the other, can be looked upon as complementary. Thus, both semantic and episodic memory might be regarded as subdivisions of a declarative system, and the PRS might be seen as one type of procedural system (Roediger, Weldon, & Challis, 1989; Squire, 1987).

AMNESIA AS A CONSEQUENCE OF DYSFUNCTION WITH RESPECT TO MAJOR PROCESSING MECHANISMS

There are several hypotheses that can be classified as explanations in terms of damage to major processing mechanisms. One such hypothesis is Cermak and Butters’ semantic encoding hypothesis (Cermak, 1979; 1989; Cermak & Butters, 1972). This hypothesis strongly emphasized encoding as the critical stage where memory disruption in amnesia occurs. However, there are several conjectures that avoid any direct reference to temporal facets of the process of remembering. One such hypothesis, which has received some attention, is Wickel grens’ associative hypothesis (Wickelgren, 1979). In keeping with traditional, associationist philosophy, Wickelgren assumed that learning involves the establishment of connections between units of behavior and knowledge. According to Wickelgren, these units are mental representations of events. Now, central to this notion is the idea that the association between units can be of two types. First, interconnections can be materialized, strengthened, or attenuated. Phenomena of this kind are crucial to classical and operant conditioning, for example. Associations of this sort are termed ‘horizontal associations’. Furthermore, when the connection between associations is made more predictive, it is said that the relation is being consolidated (Wickelgren, 1979). Second, Wickelgren also introduces associations of a second type. These latter nodes are actualized whenever one single association or node is brought about to represent the information carried by two or more other nodes. That is, associations of this second type represent more abstract, higher-order representations. Wickelgren terms these associations ‘vertical associations’. The process through which vertical associations are formed, is designated a process of chunking (Wickelgren, 1979). According to Wickelgren’s hypothesis, amnesia is related to the establishment and modification of vertical and horizontal associations. More specifically, healthy individuals can establish both types of associations. Amnesics, however, can only establish horizontal associations. This means, THE AMNESIC SYNDROME 21 that amnesics can learn simple procedural and perceptual skills, just as long as the learning process does not require the mental operations of chunking. Furthermore, it means that at least amnesics should be able to utilize information acquired prior to the onset of amnesia. Both these predictions are, of course, largely correct. Why does this inability to form chunks occur in amnesia? Wickelgren has offered a neurological answer to this question. The process of chunking is dependent upon an intact hippocampus. Although the hippocampus most likely does not function as a long-term store for information, damage to the hippocampus makes the establishment of vertical associations impossible. How does Wickelgren’s hypothesis match against rival hypothesis? The answer is probably that it does so well (Stem, 1981). The main problem with Wickelgren’s hypothesis is that it is difficult to understand how amnesics can do without chunks, at the same time as being without generalized cognitive impairment. Although amnesic patients at times have almost no records of previous experiences, it seems difficult to avoid the suspicion that intact on-line abilities necessitate at least the temporary establishment of higher-order chunks.

A m n e s ia a s a s y m p t o m o f s e l e c t iv e d is r u p t io n o f subprocesses o f REMEMBERING

The “classical” interpretation of amnesia as an instance of selective disruption of subprocesses of memory, was suggested by Milner following the examination of the patient H. M. (e.g., Milner, 1959; 1966; 1967). According to Milner’s conjecture, the amnesia of the patient H. M. was due to deficits with respect to consolidation of newly acquired information into long-term memory. This consolidation hypothesis can account for several important and striking aspects of H. M.’s amnesia. First, the consolidation hypothesis can explain why H. M. and some other amnesics perform normally on many short-term memory tasks. When information is stored in a permanent format, this process takes time - seconds, minutes, perhaps even longer. Many amnesics have normal intelligence, as measured by conventional IQ tests; this fact corresponds to the normal performance on short-term memory tasks. However, they can not (or their brains can not) convert this newly acquired knowledge into a permanent state. Second, the consolidation hypothesis can account for the fact that anterograde amnesia is far more common than retrograde amnesia. This phenomenon is brought about as a result of the possibility that consolidation takes time. Baddeley and Warrington (1970) proposed a similar explanation of the amnesic syndrome. Based upon an examination of the pattern of amnesic patients’ performance with respect to several measures of short-term memory, Baddeley and Warrington concluded that a consolidation view offered the most plausible explanation. More recently, Squire (1982a) suggested that there might exist two types of amnesia. One type of amnesia might be associated with damage to the dorsolateral thalamic nucleus. The amnesic patient N. A. and patients suffering from Korsakoff’s disease would presumably belong to this category. The other type of amnesia would be associated with dysfunction of the inferior temporal lobe. The patient H. M. would be a case at hand. In the latter case, Squire argued, an inability to consolidate information could be the locus of the deficit. According to Squire, patients with temporal lobe damage evidence more accelerated loss of information in forgetting experiments - a proposition which, however, still remains to be tested empirically. Although the consolidation hypothesis can clarify a couple of the most conspicuous symptoms occurring in the classical amnesic syndrome, the hypothesis fails to explain other typical aspects of 22 THE AMNESIC SYNDROME

amnesia. Thus, the consolidation hypothesis can not clarify why amnesic patients at times perform normally in implicit memory tasks. Similarly, the consolidation hypothesis can not disclose why amnesics are helped by retrieval cues; according to some investigators even more than controls. That is, if amnesics suffers from an inability to store material into some type of long-term memory, then it is very difficult to see why retrieval cues should be able to activate that very same information. Although consolidation theories can not account for all symptoms associated with amnesia, it should be strongly emphasized that there are certain aspects of memory dysfunction which only consolidation theories can explain. Most notably, these instances of the amnesic syndrome are the time gradients observed in anterograde and, in particular, in retrograde amnesia. That is, following an amnesic event (such as head trauma) the patient often forgets events prior to the amnesia provoking event. The duration of this retrograde amnesia varies considerably. In some cases the length of the retrograde interval amounts to seconds, in other cases the retrograde memory gap spans decades. Although the length of retrograde amnesia varies, eventually the memory trace is affected between encoding and subsequent recall attempts. Contemporary discussion about the biological and psychological mechanisms underlying consolidation can be found in, e.g., McGaugh and Herz (1972), Squire (1987), and Weingartner and Parker (1984). The second major formulation of amnesia as an example of selective disruption of subprocesses of memory, emphasizes encoding operations. According to this view, amnesic patients fail to encode to-be-remembered information. More specifically, amnesic patients fail to encode semantic aspects of to-be-remembered information. Consequently, the memories of amnesics are characterized by a certain ‘lack of meaning’ and, thus, difficult to reconstruct. The most important and substantial experimental evidence in support of this view has been provided by Cermak, Butters, and associates. Among other methods, in an impressive series of studies, these investigators have utilized Wickens’ ‘release from proactive interference’ paradigm (Wickens, 1970) and the levels-of-processing paradigm (Hyde & Jenkins, 1969; Craik & Lockhart, 1972). In both instances, Cermak and associates found that patients suffering from amnesia due to Korsakoff’s disease, evidenced attenuated sensitivity to the semantic features of to-be-remembered materials (Cermak, 1979; Cermak & Butters, 1972; Cermak, Butters, & Gerrein, 1973; Cermak, Butters & Moreines, 1974; Cermak, Naus, & Reale, 1976; Cermak & Reale, 1978). Similar to storage views of amnesia, the encoding hypothesis suffers from several significant problems. First, the outcome of several investigations has failed to provide backing for the encoding hypothesis. Thus, Myers, Meudell, and Neary (1980) found that amnesic patients could benefit from deep encoding. Similarly, Winocur, Kinsboume, and Moscovitch (1981) demonstrated that amnesics could evidence release from proactive interference, given that explicit information about the shift was provided to the subjects. Second, thè encoding hypothesis lacks a precise definition. According to the early formulations of the hypothesis, amnesics could not analyze and understand to-be-remembered material in the same manner as controls. Subsequent research has clearly demonstrated that this notion simply is not correct (Cermak, 1989; Rozin, 1976). Although patients suffering from Alzheimer’s disease or Korsakoff’s disease evidence encoding deficits of this kind, other groups of patients do not. These latter groups amount to patients suffering from herpes encephalitis (Cermak & O’Connor, 1983; Lhermitte & Signoret, 1972), ECT treatment (Squire, 1982b), and surgical removal of limbic structures (such as the case H. M.). Since amnesic patients obviously do not suffer from encoding deficits in the manner originally suggested, some writers have suggested that the encoding hypothesis should be rephrased. Thus, Cermak recently suggested that a distinction should be drawn between analysis and encoding (Cermak, 1989). The meaning of the term analysis would be close to the original meaning of the THE AMNESIC SYNDROME 23

term encoding. The term ‘encoding’ would designate the ability to convert the results of cognitive analysis to durable representations. Although this rephrasing of the encoding deficit hypothesis of amnesia obviously is an improvement, it is difficult to see exactly what a modified encoding hypothesis would add to storage or consolidation hypothesis. However, the important issue is perhaps not whether encoding or storage of information is impaired in amnesia. The main issue is probably whether the locus of the deficit in amnesia takes place at time of retrieval, or before retrieval is attempted. There are several additional variations of encoding deficit theories. The main difference between these other theories and the semantic encoding deficit hypothesis, is that the other encoding theories emphasize other types of material which amnesics can not encode. The most well known of this group of theories comes from a series of papers by Huppert and Piercy (1976; 1978b; see also Kinsboume & Wood, 1975; Hirst, 1982). According to this context hypothesis, amnesics can encode and process individual elements of an episode (i.e., the words in a to-be-remembered list of words). However, amnesic individuals are deficient when it comes to processing of contextual cues. Therefore, events can not be placed or specified with respect to when and where they took place. Consequently, the patient suffers from what appears as an inability to retrieve the appropriate information. More in detail, Huppert and Piercy (1978b) assumed that efficient encoding has two consequences. First, encoding yields the storage of multiple attributes of an item. Second, encoding results in an increase in the over-all trace strength associated with the particular item. As time passes, the two types of information are lost at different rates. Attributes are lost at a faster rate than trace strength. Therefore, when retention is tested after relatively long time intervals remembering rests relatively more upon overall trace strength. A similar phenomenon is supposed to occur in amnesia. When an amnesic patient tries to memorize a particular item, this attempt yields an increase in trace strength, but little of encoding of contextual attributes of to be remembered items. The hypothesis put forward by Huppert and Piercy is interesting, since it can explain why amnesics, despite their poor memory performance in general, at times can evidence new learning. When a subject tries to recall a particular episode, success is based upon the ability to activate attributes of the encoded events, as well as the ability to utilize the overall trace strength of the items’ representation. According to Huppert and Piercy (1978b), amnesics can only utilize the trace strength in order to support retrieval. As a result, retrieval in amnesia can take place if no referral to the encoding context is demanded by the task demands. Usually, such reference to the encoding context is not made in semantic memory tasks and in indirect tests of memory (such as in priming tasks). Of course, some amnesic patients consequently perform normally in both these latter kinds of memory tasks. Although the hypothesis offered by Huppert and Piercy emphasized encoding deficits in amnesic patients, the theory of defective processing of some aspects of stimuli is not at all logically tied to encoding operations. The inability to encode contextual features of to be remembered information, could just as well be an effect of an inability to store such information, or an inability to retrieve contextual information. Furthermore, the context hypothesis need not make any reference at all to the ‘temporal staging’ of the process of remembering. Given the emphasis placed upon interactions between encoding, consolidation and retrieval processes in modem theories about human memory (e.g., Tulving, 1983), this property of the context hypothesis put forward by Huppert and Piercy need not be a disadvantage at all. The third possibility, as envisaged by theorists adhering to one or another formulation of amnesia in terms of selective disruption of subprocesses of memory, regards retrieval operations. Amnesia might come about as the product of impaired retrieval operations. In recent research on amnesia, this hypothesis has been put forward, in particular, in a series of papers by Warrington and 24 THE AMNESIC SYNDROME

Weiskrantz (Warrington & Weiskrantz, 1968; 1970; 1971; 1974; 1978; 1982; Weiskrantz & Warrington, 1970; Weiskrantz, 1984). Support for Warrington and Weiskrantz’ retrieval hypothesis, is provided by results from the now classic investigations on picture-fragment completion and word-fragment completion in patients suffering from organic amnesia. In the late sixtieths, Warrington and Weiskrantz demonstrated that amnesic patients could improve their picture-fragment and word-fragment completion ability following exposition of target stimuli. This improvement occurred, although the amnesic patients were severely impaired with respect to remembering of the fragmented stimuli. Besides the demonstration of preserved learning in otherwise severely amnesic patients, the most interesting aspect of Warrington and Weiskrantz’ experiments regards the fact that the results seemed to indicate that the amnesics suffered from retrieval deficits. Why? Because amnesic patients could evidence new learning under some circumstances, it meant that information must have been encoded as well as stored. According to the earlier versions of Warrington and Weiskrantz’ conjecture, the retrieval deficit was a result of an increased susceptibility to interference. As a consequence of this susceptibility to interference, amnesics were assumed to lack efficient control over search and retrieval operations. In turn, the lack of efficient control caused the amnesic patients to retrieve to much information. When retrieval was constrained by means of retrieval cues, the amnesia was alleviated (Warrington & Weiskrantz, 1970). There are several problems associated with the retrieval hypothesis suggested by Warrington and Weiskrantz. First, many theorists are dissatisfied with the interference explanation connected with the original versions of the hypothesis. Although interference theory during many years influenced the psychology of learning and memory, interference explanations suffer when it comes to explaining the biology and neuropsychology of memory (McGaugh & Herz, 1972; Squire, Cohen, & Nadel, 1984). However, the retrieval account of amnesia is not at all logically connected to interference theory. In fact, Warrington and Weiskrantz have proposed a revised retrieval hypothesis, which makes no reference to interference theory. According to the modified retrieval hypothesis (Warrington & Weiskrantz, 1982), retrieval is based upon access to information in two systems. One system contains information about the strength of relation between individual items stored in memory. The basic function of this system is to modify, fine-tune and update established knowledge. This “residual system which can cope with redundancy” (Weiskrantz, 1984, p. 410) is intact in some amnesic patients. Thus, amnesics can often be able to benefit from perceptual priming, establish UCS-CS associations in classical conditioning paradigms, or learn simple rules and problem solving skills. Put in somewhat other words, amnesics can evidence spared memory functioning “...whenever an event can be predicted reliably from another”. In such situations, “...there is redundancy, and hence the possibility of automatic programming” (p. 410) The trouble in amnesia comes when the internal representations between items have to be reorganized in novel ways. This can not be achieved by amnesics. The trouble in amnesia is “...the internal cognitive relationships among items to be retrieved” (p. 410). What amnesics “...cannot learn or retain is information that requires ordering, reordering, matching, reflecting about items from store. Nor do they appear to be able toacknowledge memory for such material as they are able to acquire, which, we argue, requires an active ‘cognitive mediational system’ and which, we speculate, has become disconnected from the residual system that can cope with redundancy.” (p. 410.) That is, amnesia patients can not process features of to-be-remembered that are crucial to successful retrieval. While most theorists acknowledge Warrington and Weiskrantz’ revision as an improvement, there are still difficulties associated with the revised Warrington and Weiskrantz conjecture. Given the perspective briefly discussed above, the trouble is of course to characterize those features of THE AMNESIC SYNDROME 25 stored items which are necessary for efficient retrieval to occur. Beyond speculations, Warrington and Weiskrantz offer few clues in this regard. In this, they are, however, not different from most other amnesia theorists, irrespective of theoretical bent. The previous paragraphs have hopefully made clear that any single account of amnesia in terms of damage with respect to single subprocesses of remembering is unlikely to cover the whole story. What about combinations of the explanations discussed above? Interestingly enough, such combinations can accommodate for most aspects of human amnesia. Let it first be said that it is becoming increasingly unlikely that amnesia involves encoding deficits. Although such deficits take place in some patients (preferably patients suffering from cortical lesions, such as the frontal lobe damage seen in Korsakoff’s disease, or the parietotemporal lobe damage frequently characterizing Alzheimer’s disease victims), encoding deficits are not at all obligatory in human amnesia. Some amnesics have normal attentional and intellectual skills; therefore their encoding capacity most likely is normal. Although amnesia not by itself is a consolidation deficit, amnesics could theoretically be unable to storeaspects of remembered material. When memory is tapped explicitly, or when very little retrieval information is provided, then the rememberer must rely upon this type of information. Of course, very little is known about the character of this information. It might consist of temporal tags, or specifications of personal relevance. Just as in controls, when retrieval cues are provided, the amnesic patient sometimes can manage to activate previously acquired information. It is possible that retrieval takes place, since the retrieval cue is very akin to what can not be stored in the memory systems of the amnesic patients.

A m n e s ia a s p r o d u c e d b y d a m a g e to se l e c t iv e subprocesses o f m e n t a l FUNCTIONS, NOT SPECIFICALLY RELATED TO REMEMBERING

At least in theory, it is possible to understand amnesia in terms of disruption to selective subprocesses, not specifically related to remembering. For instance, Weiskrantz (1982) suggested that amnesia could be looked upon as an example of a specific neglect for a certain internal state, i. e. to remember. Thus, amnesia could be regarded as a specific form of agnosia; just as agnostic patients are unable to recognize aspects of the world (e.g., animals), amnesic patients can not recognize internal states. Although speculative, this hypothesis offers a novel approach to the understanding of amnesia, and certainly deserves consideration. An influential framework for research and theorizing in the cognitive sciences has been the distinction made between automatic and controlled processes (Schneider & Shiffrin, 1977; 1985; Shiffrin & Schneider, 1977) or automatic and effortfull processes (Hasher & Zacks, 1979). Briefly, these terms mean that performance in many cognitive tasks is based upon either conscious and effortful investment of attentional resources or a high degree of automaticity and over-learning. The conceptual distinction between automatic and controlled processes has been invoked to explain several striking variations in human performance. These variations amount to individual differences with respect to effects of practice, age differences in memory tasks, and forms of amnesia. Unfortunately, the distinction between automatic and controlled processes can not account for the fact that amnesics perform normally with respect to many ‘effortful’ tasks, e.g., tasks measuring fluid intelligence.

SUMMARY

This chapter has — briefly — outlined a number of important conceptualizations of amnesia in humans. The purpose of the chapter was to give a brief background to topics addressed in this 26 THE AMNESIC SYNDROME dissertation; topics related to memory impairment observed in aging and age-related neurodegenerative disorders. It is important to keep in mind that several fundamental questions regarding human amnesia have not been resolved. One reason to this state of affairs is most certainly that ‘pure’ amnesia is rare in humans. Consequently, it has not been possible to address many vital questions. Although milder memory dysfunction can differ from amnesia in important aspects, it is possible to study milder memory dysfunction as a complement to the study of the amnesic syndrome. Since milder memory dysfunction probably is more common than severe amnesia, the understanding of milder memory dysfunction is interesting in itself. The ensuing chapters summarize findings as to milder memory impairment.

CHAPTER THREE: AGE-ASSOCIATED MEMORY DYSFUNCTION

Although the amnesic syndrome has attracted profound interest among students of human memory, it is possible that the most common type of memory dysfunction is memory impairment associated with the course of aging. The purpose of this chapter is to summarize investigations regarding memory in old age. Two restrictions will be made. First, memory impairment seen in age-related neurological disorders (such as Alzheimer’s disease) will be discussed in a later chapter. Second, the discussion will deal with experimental studies, specifically. The reader is also reminded that several comprehensive reviews regarding age-associated memory dysfunction can be found elsewhere (see, e.g., Craik, 1977a; Kausler, 1982; Poon, 1985). This chapter will be organized around the following headings: (a) encoding variables, (b) retrieval variables, (c) implicit memory, (d) priming, (e) learning and conditioning, (f) metamemory, and (g) ‘learning to learn’. Next follow a discussion regarding theoretical explanations of age-related memory decline. The chapter is concluded with a review regarding age-related changes as to the central nervous system.

ENCODING VARIABLES

A common theme in contemporary studies of age-associated memory decline regards effects of factors affecting the encoding of to-be-remembered material. In general, it has been suggested that the memory decline observed in older subjects might be due to deficiencies with respect to the encoding of to-be-remembered material (e.g., Craik, 1977a; 1982; Craik and Byrd, 1982). Primarily, support for this contention comes from three types of paradigms. One kind of task that has indicated that the elderly might suffer from deficient encoding processes, regards the ‘orienting task’ paradigm of Hyde and Jenkins (1979) and Craik and Lockhart (1982). A second type of paradigm regards memory for organizable lists of words. Finally, the technique of mental imagery has been used to study encoding operations in aging. As regards ‘deep’, semantic processing, induced by means of orienting tasks, several researchers have described an age-associated deficit. As to memory for words, Eysenck (1974) and Simon (1979) both showed that elderly subjects were not aided by semantic processing to the same amount as younger adults. Similar findings have been reported by several other investigators (see Kausler, 1982, for references). Dixon, Simon, Nowak, and Hultsch (1982) demonstrated a similar deficit with respect to memory for text. Cohen and Faulkner, using a somewhat different methodology, showed that older adults were impaired with respect to the ability to recognize changes with respect to content (i.e., ‘deep’ changes). At longer time intervals, this deficit was particularly striking (Cohen & Faulkner, 1981). NORMAL AGING 27

Although these results appear to indicate that older subjects are deficient with respect to deep, semantic processing, there are several problems with this explanation. First, age-related deficits with respect to deep processing often are more pronounced if memory performance is assessed by means of free recall procedures, rather than recognition tests (Burke & Light, 1981). Second, age deficits as to deep processing can be attenuated under conditions where no memory test is expected (Perlmutter & Mitchell, 1982). Third, younger and older subjects are affected similarly by semantic relatedness in lexical decision and other priming tasks (e.g., Balota & Duchek, 1989; Bowles & Poon, 1985; Burke & Harrold, 1988; Burke, White, & Diaz, 1987; Burke & Yee, 1984; Cerella & Fozard, 1984; Howard, 1983; Howard, Lasaga, & McAndrews, 1986; Howard, McAndrews, & Lasaga, 1986; Howard, Shaw, & Heisey, 1986). If older persons suffer from semantic deficits, they do not show in priming tasks. Fourth, concerning studies of levels of processing in patients suffering from Alzheimer’s disease, older adults evidence seemingly ‘normal’ effects (Corkin, 1982; Martin, Brouwers, Cox, & Fedio, 1985; Wilson, Kaszniak, & Fox, 1980, cited in Morris & Kopelman, 1986). Finally, some researchers have described normal effects of orienting tasks in older adults (e.g., Chiarello & Hoyer, 1988). An interesting exception was also described by Barrett and Wright (1981). These researchers showed that the elderly demonstrated preserved levels-of-processing effects for words which were in vogue when the older subjects were young. Conversely, younger subjects displayed an attenuated levels-of-processing effect for these words. A possible account for the discrepancies as regards levels-of-processing effects in aging, might be that the ability to utilize semantic processing in order to support remembering is preserved when task requirements are less demanding. As described above, older adults perform in a similar manner as younger adults do, when: (a) retrieval support is provided in terms of copy cues (i.e., memory is assessed by means of a recognition test); (b) the testing procedure makes no explicit demands on retrieval (that is, when the amount of priming is used to assess ‘retention’); (c) when subjects are not engaged in active rehearsal (Perlmutter & Mitchell, 1982); (d) when the task does not require successful transfer of information from temporary to permanent storage (Cohen & Faulkner, 1981); (e) when task demands are arranged so as to allow for assessment of demented subjects; or (0 when the to-be-remembered material favours the elderly subjects (Barrett & Wright, 1981). With the exception of point (c) above, all these instances exemplify remembering under less demanding circumstances. The pattern of data as regards the levels-of-processing effect in aging suggests that older adults are capable of carrying out ‘deep’, elaborati ve processing, but that they frequently do not do so. Why? There are several tentative answers to this question. The age-associated deficit as to deep, elaborative processing, could be due to a reduction of attentional resources. Originally, this explanation was proposed by Craik (1977b). According to this hypothesis, elaborative, semantic processing is more demanding than more ‘shallow’ processing. Since older subjects are less proficient with respect to allocation of attentional resources than younger subjects, they also have difficulties engaging in semantic processing. When the conditions in which older adults evidence levels-of-processing effects are considered, it is obvious that these conditions can be classified as less demanding with respect to requirement of attentional resources. An alternative account has been to emphasize age-associated changes with respect to consolidation, retention, or retrieval of information (e.g., Burke & Light, 1981; Burke & Harrold, 1988). According to this latter view, deficits with respect to levels-of-processing are the consequence of, rather than the cause to, a memory-related deficit. That is, older individuals suffer from difficulties with respect to semantic processing because they are deficient when it comes to retrieving relevant information during processing. A second type of paradigm frequently used to investigate encoding processes, regards memory for organizable lists of words. In this type of task, subjects are presented a to-be-remembcred material which can be organized in some way. For instance, the words in a word list can be drawn 28 NORMAL AGING

from a limited number of semantic categories. At time of testing, subjects often are given several types of tests, e.g., free recall and cued recall tests, or, several free recall tests. The recall protocols from the different occasions can then be correlated to obtain a measure of the amount of clustering. Utilizing variations of this paradigm, a number of investigations have evidenced organizational deficits in the elderly (Denney, 1974; Hultsch, 1969, 1974,1975; Laurence, 1967; Mueller, Rankin, & Carlomusto, 1979; Rankin, Karol, & Tuten, 1984; Sanders, Murphy, Schmitt, & Walsh, 1980; Worden & Meggison, 1984). However, the results are less consistent regarding the functional locus of the age associated organizational deficit. Some studies indicate retrieval problems as the source of the deficit (e.g., Laurence, 1967); other data highlight encoding deficits (e.g., Denney, 1974; Hultsch, 1975). Furthermore, the organizational abilities of the elderly may be influenced by the type of material a task embraces. If the task embodies objects, the elderly categorize the items different from younger subjects (Cicirelli, 1976); if the task embodies words, older subjects and younger subjects perform similarly (Howard, 1980). The reason to this difference is not known. A third way of studying encoding operations, is by means of mental imagery. Several techniques, embodying visualization, improve memory performance in younger subjects (e.g., Bower & Winzenz, 1970; see also the discussion in Bransford, 1979). In old age, there appear to exist impairments as to the ability to improve memory performance by means of mental imagery (see Poon, Walsh-Sweeney, & Fozard, 1980 for review). However, older and younger subjects perform similarly with respect to imagery ratings of verbal materials (Kausler, 1980). Of utmost importance is the fact that older subjects can utilize imagery to foster remembering. Thus, the deficit as regards mental imagery appears to be a memory related phenomenon. In addition to the tasks mentioned above (orienting, organization, and imagery tasks), investigations of encoding in human aging have emphasized nonfocal attributes of the to-be-remembered material. Such nonfocal attributes concern the frequency of occurrence of events, physical attributes of stimuli (whether a particular word was uttered by a male or female speaker, for instance), whether the ad about the dishwasher was in today’s newspaper, or yesterday’s — to name a few examples. Memories of this type have been termed ‘rehearsal-independent episodic memory’ (Kausler, 1989); automatically encoded memory (Hasher & Zacks, 1979); or involuntary memory (Smirnov & Zinchenko, 1969). The basic idea here, is that information, such as the frequency of occurrence of an event, is automatically encoded and/or does not rely upon active rehearsal processes. Since older adults may suffer from difficulties with respect to the allocation of attentional resources, it could be hypothesized that age effects should be attenuated as to nonfocal attributes of events (Hasher & Zacks, 1979). Similarly, since older subjects most likely are deficient with respect to active rehearsal, rehearsal-independent memory could be less affected by aging. The available data suggest a relatively complex picture as to nonfocal attributes of the to-be-remembered material. Concerning frequency information, age deficits appear to exist. However, these age-related impairments are small (Attig & Hasher, 1980; Kausler & Puckett, 1980; see also Kausler, 1989, for a comprehensive discussion). A somewhat similar picture emerges as to memory for discrete actions, such as ‘mini-tasks’ or Subject-Performed Tasks (SPTs) (Cohen, 1981,1983). Some researchers have reported statistically significant age-differences (e.g., Cohen, Sandler & Schroeder, 1987; Lichty, 1986; Nilsson & Craik, 1990), others have not (Bäckman & Nilsson, 1984, 1985). In contrast to these findings, age-differences occur with respect to other forms of retrieval-independent episodic memory. As regards memory for temporal order, and memory for extended, continuous activities, age deficits are unmistakable (e.g., Kausler & Hakami, 1983; Salthouse, Kausler & Sault, 1988). It is not easy to understand why some nonfocal or rehearsal independent memories are impaired in the elderly, while others are not. Tentatively, though, older subject may suffer from deficits with NORMAL AGING 29 respect to abstraction, or the generation of inferences relevant to the situation (Hess, 1985; Zacks, Hasher, Doren, Hamm, & Attig, 1987). Such a deficit would mean little to the memory for discrete events - the information is already available. However, in order to remember the episode, the subject has to abstract information which is not readily available.

R e t r ie v a l va r ia b le s

Traditionally, an alternative to encoding explanations of older adult’s memory deficits, has been retrieval theories. That is, theories emphasizing difficulties as to retrieval of acquired information in old age.

Recall, cued recall, and recognition

A number of investigators have compared tests of free recall with tests of cued recall or recognition in young and old adults. The rationale behind such comparisons is that retrieval cues should attenuate age-associated memory dysfunction, if older subjects suffer from retrieval deficits. Explicit retrieval cues could substitute for impaired retrieval processes. It has often been demonstrated that age differences are attenuated (Ceci & Tabor, 1981; Craik, 1971; Craik & McDowd, 1987; Erber, 1974; Gordon & Clark, 1974a, 1974b; Harwood & Naylor, 1969; Howell, 1972; Hultsch, 1975; Laurence, 1967; Shaw 2i Craik, 1989; Smith, 1977, 1980; Warrington & Sanders, 1971) or even nonexistent (Sciiomleid & Robertson, 1966) when memory is assessed by means of cued recall or recognition procedures. Despite this fact, age differences are often observed in cued recall and recognition tasks. It is not known if the attenuated age differences observed in cued recall and recognition tasks are real or just the result of cued recall and recognition tasks being easier.

Recognition

Although older subjects evidence less noticeable memory deficits in recognition tasks, it should be emphasized that there really exists reliable age-differences in recognition tasks. This is obvious, particularly if the false alarm rate is considered. Although one could assume that younger subjects use a more liberal response criterion (i.e., should take more chances in guessing), quite the opposite is true. Older subjects use more lax response criteria (Ferris, Crook, Clark, McCarthy, & Rae, 1980; Harkins, Chapman, & Eisdorfer, 1979; Karlsson & Börjesson, 1990; Rankin & Kausler, 1979). Although the reason for this difference is not clear, one possibility is that the number of false alarms reflects metacognitive functions which might be vulnerable to the effects of aging.

Repeated retrieval

A less often used method to investigate retrieval processes, is the repeated retrieval paradigm, according to Tulving (1967). In this task, subjects are either presented the to-be-remembered material a successive number of times before recall. Alternatively, subjects are successive tests, instead of repeated presentations. When the two conditions are compared, a common finding is that the final performance is identical under both conditions. This outcome can be taken to mean that retrieval can aid learning and remembering. In older subjects, repeated tests seem to be less effective than repeated presentations (Crew, 1977). However, it should be noted that the study by Crew is the only age study that has utilized this paradigm. 30 NORMAL AGING

Output interference

If older subjects suffer from retrieval deficits, this could be because they are more sensitive to output interference. This phenomenon was initially described by Tulving and Arbuckle (1963). The term output interference is used to designate the possibility that (given that everything else is equal) the accessibility of a particular item is lower the more other items that are retrieved prior to retrieval of the target item. In aging, somewhat contradictory results have been reported. In an earlier investigation, Taub and Walker (1970) reported elderly subjects to be more susceptible to output interference. However, this finding was not replicated by Smith (1975). Although Smith obtained output interference for young, middle-aged, and older subjects, the magnitude of this interference was comparable in all three groups.

Retrieval from semantic memory

For a long time, retrieval from semantic memory has been considered to be spared in normally aged individuals. There are several types of evidence to support this notion. First, psychometric tests (such as the WAIS) seldom reveal age-related differences regarding many verbal tests, such as the ‘Vocabulary’ subtest (Berkowitz, 1953). Second, on some tasks developed to measure semantic memory retrieval, older adults perform similar to younger subjects (Eysenck, 1975). Third, semantic priming effects are of equal magnitude in older and younger subjects (Balota & Duchek, 1989; Bowles & Poon, 1985; Burke & Harrold, 1988; Burke, White, & Diaz, 1987; Burke & Yee, 1984; Cerella & Fozard, 1984; Howard, 1983; Howard, Lasaga, & McAndrews, 1986; Howard, McAndrews, & Lasaga, 1986; Howard, Shaw, & Heisey, 1986). This applies, even if the semantic search process involves attentional skills (Burke, White, & Diaz, 1987). The finding of equal effects of semantic priming in old and young subjects is very important. Semantic priming is believed to reflect activation of information in semantic long-term memory. In turn, activation is thought to be an integral part of retrieval of semantic information (e.g., Anderson, 1983). At the same time, there are some situations in which older subjects evidence deficits in comparison to younger subjects. Traditional measures of verbal fluency commonly display age-related deficits (e.g., McCrae, Arenberg, & Costa, 1987; Lezak, 1983; Obler & Albert, 1985; Schaie & Parham, 1977). Similarly, healthy older adults evidence impairment on certain neuropsychological language tests, such as the Boston Naming Test (Borod, Goodglass, & Kaplan, 1980; Van Gorp, Satz, Kiersch, & Henry, 1986). (The Boston Naming Test is a confrontation naming task.) Word finding difficulties are marked when subjects are asked to respond with a word to the definitiofi of the target word (Bowles & Poon, 1985). Also, word finding difficulties in natural speech are by far more frequent in older persons. Thus, older persons do evidence retrieval deficits as regards semantic memory. However, very little is known about these deficits. For instance, it is not known whether retrieval cues can aid performance in semantic memory tasks, just as the case is with respect to episodic memory tasks.

PRIMING ACROSS THE ADULT AGE SPAN

An increasing number of investigations have dealt with age-related memory impairment in terms of dissociable memory systems (Cohen, 1984; Cohen & Squire, 1980; Diamond & Rozin; 1984; Mishkin, Malamut, & Bachevalier, 1984; Tulving, 1983; 1984; Warrington & Weiskrantz, 1982; Weingartner, Grafman, Boutelle, Kaye & Martin, 1983) or in terms of dissociable memory NORMAL AGING 31 functions (Craik, 1983; Graf & Mandler, 1984; Graf, Squire, & Mandler, 1984; Jacoby, 1983; Jacoby & Dallas, 1981; Roediger & Blaxton, 1987; Scarborough, Corstese, & Scarborough, 1977; Schacter, 1987; Schacter & Graf, 1986). Aging studies have utilized different methods, such as word stem completion (Chiarello & Hoyer, 1988; Chiarello, Hoyer, & Frazier, 1987; Hoyer, Chiarello, Frazier, Palfai, & Beeber, 1986; Light & Singh, 1987), word fragment completion (Light, Singh, & Capps, 1986), homophone spelling (Howard, 1986; Rose, Yesavage, Hill, & Bower, 1986), associative priming (Howard, Heisey, & Shaw, 1986; Rabinowitz, 1986), perceptual identification (Light & Singh, 1987), picture naming (Mitchell, 1989), reading of inverted sentences (Moscovitch, 1982a; Moscovitch, Winocur, & McLachlan, 1986), and lexical decision (Moscovitch, 1982a, current dissertation). In contrast to investigations on priming and implicit memory in amnesia (see discussion above, p. 11 ff.), investigations in aging have not disclosed a uniform pattern of spared performance. There are 19 individual experiments (collected from 13 studies) addressing the question of implicit memory in normal aging. Out of these 19 experiments, the results offive experiments are indicative of impairments with respect to implicit memory in normal aging (Chiarello & Hoyer, 1988; Chiarello, Hoyer, & Frazier, 1987; Howard, Heisey, & Shaw, 1986; Moscovitch, 1982a; Rose, et al., 1986). The findings regarding impairments with respect to implicit memory come from four different research groups. All but one of these groups (Rose, et al., 1986) have also reported normal implicit memory in aging, using similar methods. Furthermore, there were slight — but statistically non-significant — differences in favour of young subjects in four experiments (Light & Singh, 1987, Experiments 1, 2, and 3; Moscovitch, 1982a, lexical decision task). Similarly, four experiments displayed non-significant differences in favour of elderly subjects. Altogether, these results could be taken to mean that there are some, but quite modest, deficiencies with respect to implicit memory in normal aging. A few commentaries could be made upon these results. First, it would not be surprising to find deficiencies with respect to performance in implicit memory tasks in a limited number of investigations, even if the hypothesized cognitive systems or biological systems subserving direct priming in episodic memory tasks were entirely intact. This is so, since implicit or indirect memory tests to some degree always involve conscious recollection (Greene, 1986; Roediger & Blaxton, 1987; Squire, Shimamura & Graf, 1985). That is, some tasks (perhaps priming involving word stems in particular) are designed in such a manner that it is unlikely that subjects without memory impairment could have forgotten larger parts of the to-be- remembered information. Instead, explicit recollection of the study material could be used to foster performance in the implicit task. The point made here — i.e., that explicit and implicit forms of memory to varying degrees always are involved in direct and indirect tests of memory — leads to a second issue. It could well be that some indirect memory tasks are better suited for the investigation of implicit aspects of remembering. Performance in word stem completion tasks shows high correlations with recall and recognition measures, whereas performance in anagram solution tasks and perceptual identification tasks are less correlated with direct memory tasks (Perruchet & Baveux, 1989). Further, some paradigms can be employed in order to calculate statistical relations between individual items tested with both direct and indirect procedures, and with repeated direct and indirect measures of memory. Perceptual identification and word fragment completion tasks have been employed in such a manner (Hayman & Tulving, 1989; Jacoby & Witherspoon, 1982; Tulving, Schacter, & Stark, 1982; Witherspoon & Jacoby, 1989). Other tasks, such as the lexical decision task and the word stem completion task, might not just as easily be tailored in this manner. The relationship between the direct and indirect tests has been investigated in one study, specifically (Light, Singh, & Capps, 1986). The results from this investigation did not evidence impairments with respect to implicit memory in the elderly. In the majority of cases, data indicative 32 NORMAL AGING

of impairments with regard to indirect tests of memory comes from paradigms where performance evidently is depending upon conscious recollection to at least some degree — the word stem completion task (Green, 1986; Squire, Shimamura, & Graf, 1985) and the free association task. A third point at hand concerns the age of the elderly subjects examined. All groups of elderly individuals tested, have mean ages of about 70 years. Experimenters investigating older subjects of higher age (e.g., above 80 years) have called the attention to continuing decrements at higher ages. In some investigations, qualitative differences between people in their seventies and people in their eighties have been demonstrated (Bäckman & Karlsson, 1986; see also discussion in Nilsson, Bäckman, Herlitz, Karlsson, Österlind, & Winblad, 1987). At present, very little is known about the consequences of very high age upon implicit memory. Presumably, findings about results from indirect memory tests in younger elderly cannot be extrapolated to the elderly of very high age. To summarize, older persons (mostly in their sixties and seventies) do evidence slight deficits on indirect tests of memory. However, the possible deficits displayed on indirect memory tests are probably not as marked as deficits seen on direct tests of memory. Moreover, it is still not clear whether the results from all indirect memory tasks can be translated into predictions about putative functional or neurobiological ”memory systems” in a simple and straight-forward way.

C onditioning a n d l e a r n in g a c r o s s t h e a d u l t a g e s p a n

In a typical learning experiment, subjects are shown a set of words, and are asked to carry out some kind of activity with these words (usually to read the words). In close association with the presentation of some of these words, an unconditioned stimulus (UCS) is presented. The UCS is usually noxious: a mild air-puff directed at the eye, a weak electrical shock, a loud sound, and so forth. If the UCS repeatedly is paired with some of the words, these will subsequently produce a physiological response, even in the absence of the UCS. It is of interest for the present purposes to note, that the testing procedures in some such tasks, are, in a sense, implicit. That is, the subject is not explicitly asked to respond in the manner the investigator encourages him to. A second reason to call the similarity between indirect tests of memory and classical conditioning into mind, is the fact that similar neural systems have been suggested to subserve both types of ”remembering”. More specifically, there is ample evidence in favour of the cerebellum as a critical structure involved in the eyelid conditioned response (McCormick & Thompson, 1984). Investigators have also at times speculated that preservation of the cerebellar cortex is critical to certain types of priming and implicit memory. On the bases of this similarity, it would be predicted that elderly persons should evidence diminished impairment in conditioning tasks of this kind. The data that have been gathered to the present date, do not support this prediction. Earlier experiments examined the classical conditioning of the eyelid response in young and older adults. The general finding was rather large decrements in the elderly (Braun & Geiselhart, 1959; Gendreau & Suboski, 1971; Jerome, 1959; Kimble & Pennypacker, 1959; Solyom & Barik, 1965). More recently, Thompson and associates (Woodruff- Pak & Thompson, 1988) have confirmed and extended these findings. In this latter study, middle aged subjects were included, in addition to younger and older subjects. Deficiencies were noted in 40 years of age, as well as in older subjects. It is clear from the studies referred to above, that deficiencies occur with respect to classical conditioning. Given the similarity between procedures involving classical conditioning on the one hand and indirect tests of memory on the other hand, this might seem surprising. However, it should be noted that the investigators utilizing classical conditioning (preferably of the eyelid response) have not compared indirect measures of learning with direct measures of learning. Thus, it might be the case that elderly subjects could be even more impaired in the latter case. This is not NORMAL AGING 33 totally unlikely. The conditioned eyelid response often occurs in the context of the subject focusing attention upon changes in the brightness of a prism. If subjects were asked to make a voluntary response — i.e., pressing a button — in the presence of a specific stimulus, it is most likely that elderly would suffer also in this task.

M etacogniiwe A s p e c t s o f R e m e m b e r in g in th e E l d e r l y

A less well-known aspect of remembering regards people’s abilities to monitor and use their knowledge and memories. Such monitoring and utilization is likely to take place in the conduct of many human activities and behaviors. Supposedly, remembering is one such activity. We might stumble around in the world, knowing hundred of thousands of isolated facts. However, if we cannot use these facts when we need them, or if we know them only when we see them, all this knowledge is of limited advantage. Similarly, if we cannot tell when we don’t know, there are small chances that we take one step back and try to adapt to this harsh fact — for instance by means of learning. Although experimental investigations regarding metacognitive aspects of remembering — or metamemory, as the term is — is a recent enterprise, several paradigms have been invented which can be used to explore aspects of metacognitive skills in remembering. Such paradigms can involve subjects making predictions at the time of study of to-be-remembered information. These predictions can, in turn, involve individual items (that is, how difficult a particular item is to remember) or mnemonic strategies (i.e., will strategy X be more efficient than strategy Y ?) Metacognitive proficiency is the determined by comparing predictions made at study with actual performance at a subsequent test. Metacognitive paradigms used in memory experiments can also comprise judgments made about information which already has been acquired. For instance, subjects will be shown questions such as “Where did Freud move when he was forced into exile?”. When subjects answer the question, they are asked how sure they are about the correctness of the answer. When subjects fail to answer a question, they are asked if they could arrive at a correct answer, given more time and perhaps one or a few hints. The results of these ratings are then compared with the results on an actual performance test. A third method is to present subjects with choices regarding strategy. In episodic memory tasks, one important factor determining performance is the type of activities subjects are engaged in at time of study, at time of test and in the interval in between. An important metacognitive skill is probably the ability to select an efficient strategy, and to change strategy when the old one becomes obsolete. It could very well be that certain age-deficits are due to difficulties in finding the appropriate strategy in the right situation. When it comes to normal aging, metamemory has been addressed in eleven papers. As to the methods employed, these investigations embrace strategy mediated vocabulary learning (Brigham & Pressley, 1988), prediction of learning of paired associates (Bruce, Coyne, & Botwinick, 1982), prediction of serial picture span recall (Murphy, Saunders, Gabriesheki, & Schmitt, 1981), word recall (Perlmutter, 1978; Shaw & Craik, 1989), word recognition (Perlmutter, 1978), recall of letter series (Lachman & Jelalian, 1984), vocabulary tests (Lachman & Jelalian, 1984), historical knowledge (Perlmutter, 1978), feeling-of-knowing of general knowledge (Bäckman & Karlsson, 1986; Lachman & Jelalian, 1984; Lachman, Lachman, & Thronesberry, 1979), matching of paired associates (Lovelace & Marsh, 1984; Rabinowitz, Ackerman, Craik, & Hinchley, 1982), And comprehension of prose (Zabrucky, Moore, & Schultz, 1987). Again, it must be concluded that the outcome is varying. There is a total of thirteen experiments, adapted fi-om eleven original research papers mentioned above. The greater pan of these investigations — i.e., seven experiments — have yielded results indicating that there are no statistically significant differences between the young 34 NORMAL AGING

and the elderly with respect to metamemory (Bäckman & Karlsson, 1986; Lovelace & Marsh, 1984; Perlmutter, 1978; Rabinowitz, et al., 1982; Shaw & Craik, 1989; Zabrucky, Moore, & Schultz, 1987). Two investigations have reported older subjects to outperform younger subjects (Lachman & Jelalian, 1984; Lachman, Lachman, & Thronesberry, 1979), and four experiments have demonstrated deficits in the elderly with regard to metamemory (Brigham & Pressley, 1988; Bruce, Coyne, & Botwinick, 1982; Lachman & Jelalian, 1984; Murphy, et al., 1981). The overall pattern, namely 2-7-4, seem to indicate that there are no deficits in the elderly with respect to metamemory. Although four experiments suggest metamemorial deficits in the aged, this result is almost perfectly outbalanced by the two experiments where the elderly outdid the young. Unfortunately, this conclusion might be premature. As noted in previous sections as well, the mean age of the elderly participants in most studies is about 70 years. However, most people in modem society live significantly longer than this. Medical, social, and neuropsychological problems in the elderly do seem to increase dramatically around the beginning of the ninth decade of life. Thus, it might not come about as surprising that modest deficits are found in the 70 years old — if there are any deficits whatsoever. This should, of course, not be taken to mean that there actually are deficits with respect to metamemory in ”older” elderly persons. However, it should be taken as a caution to extrapolate from findings in 70 year old individuals to individuals of higher age. A second reason to doubt the inference of preserved metamemory skills in the aged, comes from a task analysis of the methods employed in the experiments discussed. It is possible to group the studies according to whether metacognition involves (a) predictions about performance in a particular task, (b) predictions regarding a subjects ability to gain access to information already acquired — ”postdictions” as Brigham and Pressley (1988) coined the term, and (c) learning of strategies, which might benefit acquisition and utilization of remembered materials. If the findings are looked upon in this way, there is a case for an absence of aging effects in tasks involving postdictions regarding previously acquired information (Bäckman & Karlsson, 1986; Lachman & Jelalian, 1984; Lachman, et al., 1979; Lovelace & Marsh, 1984; Perlmutter, 1978; Rabinowitz, et al., 1982; Zabrucky, et al., 1987). On the other hand, metamemory tasks involving predictions about accuracy before learning (Bruce, et al., 1982; Lachman & Jelalian, 1984; Murphy, et al., 1981) are suggestive of age deficits. Regarding investigations involving strategy learning, very few investigations have been conducted to this date. One of these investigations is suggestive of marked age deficits with regard to strategy acquisition (Brigham & Pressley, 1988). The second experiment of this kind did not reveal age deficits (Shaw & Craik, 1989).

A b il it y o f *Le a r n in g t o Le a r n ' in o l d a g e

A topic common in the psychology of learning, is the question of learning to learn. That is, learning and memory requires only to a small extent the mere registration of information. Typically, passive, “rote” rehearsal is a useless learning strategy. Therefore, one of the main facets of effective learning is the ability to develop efficient strategies for memorization and learning. Psychologists speak of phenomena of this kind in terms oftransfer of cognitive skills from one situation to the next (see Bransford, 1979). Clearly, one of the roots of memory difficulties could be the very fact that people suffering from memory deficits are not as apt as healthy, younger adults in this regard. It is also obvious that the question of transfer of cognitive skills is closely related to metacognitive aspects of remembering and learning. Unfortunately, there are very few investigators who have addressed this topic explicitly to this date. In fact, Kausler (1982) discovered only one study explicitly addressing the question of transfer in adult age which fully met the conceptual demands of a transfer experiment. NORMAL AGING 35

Freund and Witte (1976) used a paired-associates learning paradigm to investigate the question of transfer in old age. Subjects studied a list of paired-associates (e.g., “ground - cold”) until a criterion of one errorless trial was fulfilled. After the learning of a set of word pairs, one of three things could take place. In one of the three experimental conditions, younger and older subjects studied paired-associates, where the stimuli (or retrieval cues) were identical to stimuli in the preceding list. The response items (i.e., the targets), however, were new and had not been encountered in the experiment (for instance, “ground - cat”). In the second condition of the experiment, subjects studied paired-associates that had not been in the first list. Finally, in the third experimental condition, subjects studied paired-associates in which the first word (e.g., “ground”) had been encountered previously, and the second word was novel but related to the original response/target (e.g., “ground - chilly”). This design allows for the examination of two types of transfer effects. First, the performance might be hampered when items of the type “ground - cat” are studied. This is an example of negative transfer . The second transfer phenomenon is due to the study of items such as “ground - chilly”. Here learners can utilize their recent experience with highly similar material in order to improve performance. That is, if the word-pair “ground - cold” has been acquired subsequent to learning of the first list, it simply might become easier to learn the association “ground - chilly” during study of the second list. This is an example ofpositive transfer. As to aging, there is some evidence in favour of negative transfer in older subjects. Furthermore, the magnitude of this disruption is larger for the elderly than for the young (Arcnberg, 1967; Hulicka, 1967; see also Kausler, 1982, pp. 405 ff.). From this, one could be led to conclude that one source of cognitive impairment is larger negative transfer effects. However, this phenomenon might also be brought about by larger positive transfer effects in the young subjects. The investigation by Freund and Witte (1976) tested this possibility. Interestingly enough, these authors found no evidence for altered transfer effects in the elderly. Thus, transfer effects could be relatively spared in the elderly. Although this study made an effort at testing sources of putative age-effects upon transfer, it should be regretted that the investigators did not use lists of equal length for young and elderly subjects. Thus, the study of transfer and metacognitive aspects of learning is still, largely, unexploited. It should be emphasized that transfer also can be understood in terms of specific and nonspecific transfer (Kausler, 1982). Specific transfer is studied in the experiments referred to above. It takes place as a result of some kind of relation between items in the to-be-remembered (or “to-be-learned”) information. Nonspecific transfer, on the other hand, is brought about as a result of the circumstances surrounding the testing situation. Effects of non-specific transfer has rarely been studied in the context of aging.

THEORIES OF AGE-ASSOCIATED AMNESIA

In general, there exist relatively few specific theories about memory in old age. Perhaps rightfully so, most theories about amnesia can be applied to memory dysfunction taking place in the elderly. That is, it is possible that the same kind of amnesia is seen in aging and in organic amnesia. However, still a few theories have been advanced as to the fate of memory in old age.

‘PROCESSING 9 THEORIES

A common explanation of age-associated memory loss, is about processing deficits in old age. This hypothesis, which has grown out of the ‘levels-of-processing’ framework, emphasizes a ioss 36 NORMAL AGING

of analyzing capability in the elderly. Due to this deficit, older subjects fail to analyze to-be-remembered information in an optimal way (e.g., Craik & Byrd, 1982). Often, the processing deficit is understood in terms of depleted attentional resources.

Sp e e d o f n e u r o n a l p r o c e s s in g

An alternate explanation to the processing/encoding account, emphasizes a putative loss of cognitive speed in old age (Birren, 1974; Salthouse, 1982). According to this view, the aging brain is charactherized by an altered signal-to-noise ratio. The signals of neurons involved in specific processing will become weakened relative to background noise. As a consequence, it will take longer to decipher a regular pattern. Consequently, older subjects will display a loss of cognitive tempo.

THE NEUROBIOLOGY OF NORMAL AGING AND DEMENTIA

Thus far, this chapter has pointed out areas where researchers have studied memory impairment in the aged. Although a number of experimental investigations regarding memory impairment have been published in recent years, relatively little - surprisingly little - is known about neurobiological alterations in the aging brain (e.g., Fredericks, 1985). In particular, this is true regarding the relation between neurobiological changes and psychological alterations. In neurodegenerative disorders, an initial body of knowledge has been gathered as to the relation between neurochemical alterations and cognitive symptoms. Thus, in Alzheimer’s disease, the central cholinergic deficit appears to be related to memory dysfunction (Kopelman, 1986) and possibly constructional apraxia as well (e.g., Muramoto, Sugishita, & Ando, 1984). In schizophrenia, dopaminergic deficits are correlated to aspects of frontal-lobe dysfunction. At present, there are no such relatively clear correlations between neurological alterations and cognitive deficits in normal aging. In part, this result stems from the fact that biological alterations with respect to the central nervous system are less marked in normal aging than in many neurodegenerative disorders. Despite this obvious fact, several alterations with respect to the central nervous system have been described in older people. Which alterations? Earlier work, conducted before the appearance of contemporary imaging techniques, such as the CT-scan, emphasized analysis of neural tissue obtained post-mortem. Thus, it has been known since long (von Braunmühl, 1957) that the weight of the brain shows a slow, but steady decline that begins between the second (Debakan & Sadowsky, 1978) and third (Peress, Kane, & Aronson, 1973) decades of life. Obviously, it would be very interesting to know if general changes with respect to brain weight can be related to cognitive changes. However, it should be noted, that some investigators have noted that the reduction in brain weight might be determined by loss of white matter (Miller, Alston, & Corsellis, 1980) rather than grey matter. This could be taken to mean, that these changes have relatively benign consequences, as regards cognitive functioning. The drop in brain weight across the adult age span is correlated with two other gross anatomical changes: dilatation of the cerebral ventricles, and gyral atrophy. On the CT, dilatation of the lateral ventricle is observed from about 40 years of age (see, e.g., Barron, Jacobs, & Kinkel, 1979). However, there are marked individual differences, and consequently considerable over-lap between age groups, regarding this measure. It is not known, whether dilatation of the cerebral ventricles is related to any specific cognitive or behavioral measure. Earnest, Heaton, Welkinson, and Manke (1979) and Soininen, Puranen and Reikkinen (1982) documented correlations between ventricular enlargement and various neuropsychological tests. Unfortunately, such tests reveal little about basic cognitive mechanisms. NORMAL AGING 37

Rather, conventional neuropsychological testing provides a global index regarding the functional integrity of the central nervous system. Tentatively, it could be hypothesized that the dilatation of the lateral ventricle is related to the appearance of global cognitive reduction in older-older individuals. For instance, Barron, Jacobs, and Kinkel (1979) noted an accelerated increase in the size of the lateral ventricle on CT-pictures obtained from subjects older than eighty years. During this phase of the process of aging, a marked drop in cognitive capacity is observed. Unfortunately, little is known about the underlying events that produces ventricular dilatation in the aged. A similar picture emerges, as regards gyral atrophy. Gyral atrophy can be observed at about forty years of age, and it is then significantly correlated with the age of the subject (Carlen, Wilkinson, Wortzman, Holgate, Cordingley, Lee, Huszar, Moddel, Singh, Kiraly, & Rankin, 1981; Freedman, Knoefel, Naeser, & Levine, 1984). Although some earlier investigators described a pattern of generalized gyral atrophy in some elderly persons (von Braunmühl, 1957), most research supports the claim that gyral atrophy is selective. Thus, gyral atrophy is marked in the parasagittal region. This pattern apparently holds for post mortem data (Hooper & Vogel, 1976; Tomlinson, Blessed, & Roth, 1968), as well as neuroradiological studies (Gyldenstedt, 1977). While there is some degree of widening of sulci in normal aging, it should also be reminded that at least one large scale study have described that the interhemispheric fissure in the frontal region is even more enlarged that the cortical sulci (Cala, Thickbroom, Black, Collins, & Mastaglia, 1981). In contrast to the aforementioned aspects of the neurobiology of the brain, the width (or thickness) of the cortex is unaffected in the aging process. Henderson, Tomlinson and Gibson (1980) failed to document any difference taking place between 16 to 95 years of age in their series of 66 brains. The results from this extensive investigation thus replicate earlier findings (e.g., Brody, 1955). It follows, that the aging process has diverse effects upon different aspects of the integrity of the central nervous system. The diverse consequences of human aging are even more clear when neuronal cell loss is considered. Brody (1955), Colon (cited in Kemper, 1984) and Shefer (cited in Kemper, 1984), all provided cell counts of multiple cytoarchitectonie areas of the neocortex. In general, cell loss varying between 20 to 30 per cent was observed in frontal and temporal association areas, whereas less pronounced alterations (10 to 15 per cent) were observed in primary cortical areas. In allocortex, several researchers have documented losses ranging between approximately 20 to 30 per cent (Ball, 1977; Dam, 1979). With respect to subcortical structures and the brain stem, a complex picture emerges regarding cell loss. In the amygdala, Herzog and Kemper (1980) described reductions of about 5 to 20 percent for the cortical, medial central, and central nuclei. Interestingly enough, all other nuclei of the amygdala were unaffected by the process of aging. In the basal ganglia, Bugiani, Salvarmi, Perdelli, Mancardi, and Leonardi (1978) described a correlation between age and cell per unit volume amounting to -.62 for small cells, and -.36 for large cells. Put in other terms, the reduction was 30 per cent for small cells, and 27 per cent for large cells. These changes should be evaluated in the light of striking reductions of dopaminergic neurons in substantia nigra. McGeer, McGeer, and Suzuki (1977) estimated the correlation between age and the number of cells to -.83. These authors suggested that the loss of dopaminergic neurons in aging could be responsible for alterations of gait and posture seen in aging. As regard cell loss in the putamen, this phenomenon might serve to compensate for the loss of dopaminergic input in the extrapyramidal system (Bugiani, Salvarmi, Perdelli, Mancardi, & Leonardi, 1978). There is also a distinct loss of (preferably noradrenergic) perykaria in the locus coeruleus (Bondareff, Mountjoy, and Roth, 1982; Brody 1976; Bugiani Sal vanni, Perdelli, Mancardi, and Leonardi, 1978; Tomlinson, Irving, and Blessed, 1981; Vijayashankar and Brody, 1973; 1979). 38 NORMAL AGING

Based upon data from several investigations, the magnitude of this cell loss can be estimated to be within the range 30 to 50 per cent at the age of 90 (Kemper, 1984). The loss of neurons in the locus coeruleus merits consideration, since noradrenaline (the mayor neurotransmitter of the locus coeruleus) has been implied in several aspects of attention (e.g. Archer, Järbe, Mohammed, and Priedite, 1985; Lorden, Rickert, Dawson, and Pelleymounter, 1980), learning (e.g. Archer, Ögren, Ross, and Johansson, 1982; Sarah, 1985), memory (McEntee and Mair, 1980), anxiety (Britton, Ksir, Thatcher-Britton Young, and Koob, 1984; Tombaugh, Pappas, Roberts, Vickers, and Szostak, 1983) and neuronal plasticity (e.g., Kasamatsu, 1983). Since some of these aspects of the function and capacity of the brain are altered in aging, noradrenaline might be directly involved. In normal aging, cell loss has also been noted in the facial nerve nucleus (Maleci, 1934; cited in Hanley, 1974) and with respect to the Purkinje cells of the cerebellum (Hall, Miller and Corsellis, 1975). In contrast to the findings related thus far, researchers have not found age-related cell loss in many other subcortical and brain stem areas. These areas include the mamillary bodies, the supraoptic and paraventricular nuclei of the hypothalamus, the roof nuclei of the cerebellum, and several brain stem nuclei (see Kemper, 1984, for review). Thus, in order to summarize the age-related changes as regards cell loss, it can be stated that “...cell loss with increasing age appears to be widespread in cortical and hippocampal areas, whereas in other areas of the brain it is selective, affecting the striatum, the phylogenetically older regions of the amygdala, the facial nerve nucleus, the monoaminergic nuclei of the brain stem, and the Purkinje cells of the cerebellum” (Kemper, 1984, p. 15). Thus far, quantitative aspects of cell loss in normal aging have been discussed. However, there are also changes with respect to the size of neurons, neuronal processes, and organelles. With respect to the size of neurons, reductions have been noted to occur in the subiculum after the age of 50, at frontal cortical sites around 65 years of age, and in brain-stem nuclei after the age of 80 years (Uemura and Hartmann, 1978a; 1978b; 1979). Mann and associates have provided information regarding nuclear and nucleolar size. With respect to the former parameter, reductions in temporal lobe pyramidal cells have been reported to take place in subjects 78 years and older (Mann, Neary, Yates, Lincoln, Snowden, and Stanworth, 1981). As to nucleolar size, age-related changes have been observed with respect to Purkinje cells, hippocampal pyramidal neurons, and in certain brain­ stem nuclei (Mann, Yates, and Stamp, 1978). It is commonly assumed that the structure of the interconnections between neurons is important to memory and learning. Therefore, changes affecting neuronal processes should be of particular interest. In a now classical series of investigations, the Scheibels described a characteristic pattern of changes in relation to advancing age (Scheibel, Lindsay, Tomiyasu, and Scheibel, 1975; 1976; Scheibel, Tomiyasu, and Scheibel, 1977). Following an irregular swelling of the cell body and apical shaft, spines were lost, and the dendritic network was reduced. In an end stage, the apical shaft disappeared. These changes were noted in the temporal, frontal and motor cortex, and the hippocampus. The most striking alterations were noted with respect to the large Betz cells of the motor cortex. So far, the discussion about cell loss in normal aging has concerned the fate of neurons at various sites in the central nervous system. Concerning glial cells, there appears to be a reduction as well. Henderson, Thompson, and Gibson (1980) reported losses in older persons. However, the loss of glial cells might not be as apparent as the loss of neurons. The course of human aging is typically associated with changes with respect to white matter. On the CT or MRI, leukoaraiosis — the occurrence of white matter lucencies (Steingart, Hachinski, Lau, Fox, Diaz, Cape, Lee, Inzitari, and Merskey, 1987; Steingart, Hachinski, Lau, Fox, Fox, Lee, Inzitari, and Merskey, 1987) — is relatively common (15-20 per cent) in non-demented elderly NORMAL AGING 39

(Prencipe & Marini, 1989). Furthermore, so called CT density numbers of white matter are decreased with increasing age (Zatz, Jemigan, and Ahumada, 1982). These clinical findings are in close agreement with neuropathological results. Miller, Alston and Corsellis (1980) described an increased grey-white matter ratio with advancing age. Kemper (1984) reviewed several older studies and reexamined the Yakovlev collection. He concluded that marked changes occur in fiber systems undergoing long postnatal cycles of myelination. That is, the reticular formation, association and limbic cortices clearly evidence demyelination, while the primary cortices, the visual radiation, and internal capsular fibers do not. In other words, the loss of white matter in old age apparently follows Ribot’s law. All aspects of the neurobiology of aging discussed so far, have regarded reductions, things that ‘go down’ with increasing age. What ‘goes up’ with aging? A typical symptom of aging is the accumulation of material at various sites in the nervous system. The accumulation of lipofuscin (lipofuscinosis) is one of the most apparent changes taking place in aging. Lipofuscinosis represents the accumulation of lipid pigments in the cytoplasm of the cell. Lipofuscinosis is observed, not only in normally aged mammals, but also in several neurodegenerative disorders affecting animals and man. While accumulation of lipofuscin accelerates across the adult age span, a relationship with functional changes has not been demonstrated consistently. Researchers have demonstrated improvement of memory and learning in laboratory animals, as well as impairment, in conjunction with lipofuscinosis (Lai, Pogacar, Daly, and Puri, 1973; Nandy, 1978). Deposition of lipofuscin is not implicated in Alzheimer’s disease. However, the co-occurrence of lipofuscinosis and dementia in conjunction with certain forms of inborn errors of metabolism (e.g., Kuf’s disease), makes it likely that lipofuscin impairs the normal function of neurons. In aging, there is also an increase of melanin pigmentation. This change affects selected (predominantly) monoaminergic structures: substantia nigra and the locus coeruleus (Mann & Yates, 1974). Although accumulation of lipofuscin and melanin take place in aging, these changes might be relatively benign. In contrast, several changes indicative of Alzheimer’s disease, Parkinson’s disease, and other, related conditions, are seen in the non-demented elderly. The single alteration that perhaps is given the largest attention at this moment, is the senile (or neuritic) plaque. As discussed elsewhere in this report, the senile plaque is abundant in patients suffering from Alzheimer’s disease. However, this lesion is also found in animals and non-demented people. In human aging, senile plaques appear around the age of 50 (Jordan, 1971). Hereafter, the number of plaques is positively correlated with chronological age. At the age of 90, about 70 per cent of brains evidence senile plaques (Jordan, 1971). It should be emphasized that the number of senile plaques is relatively few in non-demented individuals. When plaques appear, they are most abundant in the parahippocampal and fusiform gyri (Matsuyama and Nakamura, 1978). The senile plaque is most likely very important as regards cognitive changes seen in human aging and age-correlated neurological disorders. Not only is the senile plaque abundant in Alzheimer’s disease; recently, Fuld and co-workers described a correlation between plaque counts and memory performance in non-demented elderly (Fuld et al., 1987). However, at the moment, fairly little is known about this lesion in relation to aging. The second hallmark of Alzheimer’s disease is the neurofibrillary tangle (see discussion elsewhere for explanation). In aging, this intraneuronal structure appears during the fourth decade of life (Matsuyama and Nakamura, 1978). After the age of 80, most researchers have described neurofibrillary tangles in almost all human brains (Alafuzoff, 1985; Blessed, Tomlinson and Roth, 1968; Jordan, 1971; Matsuyama and Nakamura, 1978; Tomlinson, 1980; however, see also Dayan, 1970; and Ulrich, 1982, for conflicting results). 40 NORMAL AGING

Interstingly enough, neurofibrillary tangles show a strong predilection for the hippocampus and the enthorinal cortex (Alafuzoff, 1985; Ball, 1976; 1978; Kemper, 1978; Matsuyama and Nakamura, 1978), the locus coeruleus (Forno and Alvord, 1971; Tomonago, 1979; 1981) and the substantia nigra (Forno and Alvord, 1971). However, neurofibrillary tangles are rare, and frequently even lacking, at most other sites in normal aging. For instance, in the neocortex of older subjects, the prevalence of neurofibrillary tangles is lower than one per cent (Alafuzoff, 1985; Matsuyama and Nakamura, 1978). It is tempting, therefore, to suggest that the occurrence of neurofibrillary tangles in the neocortex is crucial to the symptoms of dementia. That is, elderly non-demented subjects evidence several neurobiological deficits, such as the occurrence of senile plaques, and several neurochemical alterations (see below). These changes are presumably responsible for age-related cognitive changes, such as memory dysfunction. However, cognitive differences between non-demented and demented elderly might be attributable to the occurrence of neurofibrillary tangles in the neocortex. Such cognitive differences could, tentatively, be deficits with respect to language, visuo-spatial skills, and attentional capacity. A third lesion, relatively less frequent in aging, as well as in Alzheimer’s disease, is the appearance of granulovacuolar degeneration. This lesion is uncommon before the age of 60. After this age, granulovacuolar degeneration is observed in 20 per cent of non-demented subjects (Dayan, 1970). In older subjects, the prevalence is higher (Tomlinson and Kitchener, 1972). However, a strict association between granulovacuolar degeneration and increasing age has at times been difficult to certify (Ball and Lo, 1977; Peress, Kane and Aronson, 1973). It should also be emphasized that granulovacuolar degeneration is a lesion primarily seen in the hippocampus (Ball and Lo, 1977; Hooper and Vogel, 1976; Tomlinson and Kitchener, 1972). In addition, granulovacuolar degeneration is seen only in humans. In contrast to granulovacuolar degeneration, there is a clear correlation between age and the emergence of so called Hirano bodies. Similar to granulovacuolar degeneration, Hirano bodies are intracytoplasmic inclusion bodies. In addition, Hirano bodies show a strong predilection for Sommer’s sector of the hippocampus (Kemper, 1984). Hirano bodies appear relatively early in adult life — in the second decade (Ogata, Budzilovich, and Cravioto, 1972). During the seventh decade, an increase is seen. In subjects 80 years and older, Hirano bodies are always observed (Ogata, Budzilovich, and Cravioto, 1972). In addition to human aging and age-associated neuro-degenerative disorders (such as Alzheimer’s disease and Pick’s disease), Hirano bodies are also seen in transmissible dementias in man (kuru), primates (kuru), and mice (scrapie). With respect to Hirano bodies and granulovacuolar degeneration, very little is known about the contribution of these inclusions to cognitive and behavioral alterations seen in aging and dementia. A final type of inclusion that should be mentioned, is the Lewy body. Lewy bodies are typically frequent in monoaminergic brain stem nuclei in Parkinson’s disease. However, Lewy bodies also occur in Alzheimer’s disease, several types of “subcortical” dementia and, occasionally, in normal aging. Since Lewy bodies appear in Parkinson’s disease, several large-scale studies have estimated the frequency of this lesion in healthy subjects as well. Older investigations have generally estimated the incidence to about 4.5 per cent (Kemper, 1984); while more recent investigations have come up with somewhat higher estimates, about 10 per cent (Forno and Alvord, 1971; Tomonago, 1979). The latter writer also estimated that Lewy bodies appear in one third of subjects in the tenth decade of life. A conspicuous sign in patients with Parkinson’s disease is bradyphrenia, i.e., mental slowing. Therefore, it is possible that the appearance of Lewy bodies and associated damage to monoaminergic neurons, might contribute to the ‘speed loss’ ascribed to human aging. In addition, NORMAL AGING 41 it is possible that the appearance of Lewy bodies contributes to rigidity and other neurological symptoms at times observed in the elderly. Apart from the synaptic changes mentioned, little in the discussion of neurobiological changes in human aging has touched upon alterations that have a direct bearing upon behavioral and cognitive changes. In this regard, alterations of neurotransmitters are particularly interesting. In general, a whole body of knowledge has been gathered with respect to many of the ‘classical’ neurotransmitters, and the monoamines in particular. This is probably due to two factors. First, there are reliable methods available for measuring these neurotransmitters. Second, some of the ‘classical’ neurotransmitters have been implicated in several important neurological and psychiatric disorders. For instance, noradrenaline and serotonin have been implicated in depression; dopamine in Parkinson’s disease and schizophrenia; and acetylcholine in Alzheimer’s disease, dementia, and memory dysfunction. Usually, neurotransmitter activity in the human brain can not be investigated directly. Therefore, most studies have assayed levels of transmitter-related enzymes. As regards the catecholamines (i.e., dopamine, noradrenaline, and adrenaline), several groups have documented increases of monoamine oxidase in older subjects (e.g., Robinson, Nies, Davies, Bunney, Davis, Colburn, Bourne, Shaw, and Coppen, 1972; Gottfries, Orland, Wiberg, and Winblad, 1975). This enzyme is involved in the degradation of catecholamines; thus an increase in monoamine oxidase would yield a reduction of transmitters at the synapse. However, it is important to note that the largest increase in monoamine oxidase levels take place earlier during life (Samorajski and Rolsten, 1973). Enzymes involved in the synthesis of catecholamines are most likely affected in the aging process. This applies to DOPA decarboxylase and, in particular, to tyrosine hydroxylase (McGeer, 1978). Two things are important in this regard. First, depletion of catecholamine synthetic enzymes is marked in regions containing relatively high densities of dopaminergic processes. Thus, depletion of catecholamine synthetic enzymes might be directly related to loss of dopaminergic neurons in the substantia nigra (McGeer, 1978; see also discussion above). Second, the reduction with respect to tyrosine hydroxylase is actually decelerated in older subjects. A dramatic reduction of catecholamine synthetic enzymes occurs before the fourth decade of life. While this drop continues at later ages, it is not as pronounced as in younger subjects (McGeer, 1978). While DOPA decarboxylase and tyrosine hydroxylase are affected by the process of aging, dopamine-b-hydroxylase might be more resistant to age (Grote, Moses, Robins, Hudgens, and Croninger, 1974). Dopamine-b-hydroxylase is involved in converting dopamine to noradrenaline. Thus, it could be that at least partly a putative noradrenergic deficit in aging is due to deficient processing of dopamine. Levels of the catecholamines are difficult to assay directly. However, a few investigations have documented age-associated reductions of catecholamines in the basal ganglia and in the hippocampus (Carlsson and Winblad, 1976; Gottfries, 1986; McGeer and McGeer, 1976). In the investigation by Gottfries (1986), age-associated depletion of dopamine and noradrenaline was more pronounced than the drop with respect to homovanillic acid (HVA) and 3-methoxy 4-hydroxyphenylglycol (MHPG). (HVA and MHPG are the mayor metabolites of dopamine and noradrenaline, respectively.) This latter Finding to be taken to indicate that there is a compensatory increase in turn-over of catecholamines, as a response to loss of neurons. A somewhat more muddled picture emerges as to serotonin, serotonin metabolites, and enzymes involved in the metabolism of serotonin (McGeer, 1978; Selkoe and Kosik, 1984). Thus, 5-hydroxyindolacetic acid (5-HIAA), the major metabolite of serotonin, might be unaffected by the aging process. In contrast, Gottfries and associates have described a drop with respect to serotonin in the caudate nucleus, but not in the hippocampus (Gottfries, 1986). The possibility of age-related changes with respect to central serotoninergic systems is supported byin vivo studies of serotonin 42 NORMAL AGING receptor binding, using positron emission tomography. Recently, Wong and associates (Wong, Wagner, Dannals, Links, Frost, Ravert, Wilson, Rosenbaum, Gjedde, Douglass, Petronis, Folstein, Toung, Bums, and Kuhar, 1984) demonstrated reduced receptor binding in the caudate nucleus, the putamen, and the frontal cortex. The central cholinergic system is most certainly affected in the process of aging, although the changes are not as conspicuous as in certain neurodegenerative disorders, such as Alzheimer’s disease, Pick’s disease, Parkinson’s disease with dementia, and Korsakoff’s disease. This cholinergic depletion is seen as reduction of choline acetyl transferase in the neocortex (e.g., Bartus, Dean, Beer, and Lippa, 1982; McGeer, 1978). In humans, there is also a drop with respect to choline acetyl transferase in the caudate nucleus. However, this alteration is marked during the first two decades of life rather than during old age (McGeer, 1978). In contrast to the ‘classical’ neurotransmitters, less is known as regards age-related alterations of the most abundant neurotransmitters in the human neocortex, i.e., glutamate, aspartate, and GABA. Since some of the mental changes seen in aging might be brought about as a consequence of alterations with respect to neurotransmission, investigations addressing these issues are of utmost importance. However, the GABA-ergic systems of the brain seem to undergo age-related changes. Glutamic acid decarboxylase, an enzyme which synthesizes GABA, is reduced in aging. These changes are seen in the caudate nucleus, the putamen and, in particular, the thalamus (Cote and Kremzer, 1983; McGeer, 1978). Relatively little is also known about age related changes of neuropeptides. Many abundant neuropeptides, such as somatostatin, neuropeptide Y, delta-sleep inducing peptide, and b-endorphin are, as a mie, considered to be unaffected by aging. Vasoactive intestinal peptide has been reported to increase in older subjects (Perry, Blessed, Tomlinson, Perry, Crow, Cross, Cross, Dockney, Dimaline, and Arregui, 1981), although it is not known whether this increase is specific to certain regions of the central nervous system. In the cerebrospinal fluid, cholecystokinin also shows a weak, positive correlation with increasing age (Gjerris, Rafaelsen, S0rensen, Bryld, Lykke-Olesen, Werdelin, and Rehfeld, 1985). Substance P and neurotensin might be reduced in the putamen and substantia nigra, respectively (Buck, Deshmukh, Burks, and Yamamura, 1981). To summarize the neuroanatomical and neurochemical changes observed in normal aging, it can perhaps be said that aging is marked by two things: a loss of neurons, neuronal processes, and consequently, neurotransmitters; and an increase of various kinds of inclusions, most of which are endogenous proteins. It is likely that these two types of changes somehow ‘go together’. However, it is not known whether they are causally related (i.e., the accumulation of amyloid could give rice to dystrophic alteration of nerve cells; or cell damage could provoke production of amyloidogenic proteins) or whether they both are symptoms of underlying, as of yet unidentified, events. The changes seen in aging do not affect the central nervous system uniformly. The association areas of the neocortex, the allocortex, and monoaminergic brain stem nuclei are particularly affected. Therefore, it might be said that the type and localization of lesions occurring in normal aging bear some resemblance with changes seen in Alzheimer’s disease, and, to some extent, Parkinson’s disease. A second conclusion proposed, is that the age-related changes in the human central nervous system are less marked the closer one gets to the functional integrity of the brain. That is, age- associated impairment can be fairly easily demonstrated as regards the gross morphology of the brain. However, when neurotransmission is concerned, age-associated changes are far from arresting. This possibility could be taken to mean two things. First it might mean that the functional integrity of the brain is well preserved in normal aging. Second, it could mean that anatomical changes occur after neurochemical changes. As already mentioned, the most striking neurochemical reductions take place during the first three decades of life. NORMAL AGING 43

As always, when the course of normal aging is discussed, it should be underscored that there is considerable individual variation with respect to the changes indicated above. Therefore, in many regards there is considerable overlap between healthy, older subjects, and younger subjects.

CHAPTER FOUR: AMNESIA IN NEURODEGENERATIVE DISORDERS AND OTHER CONDITIONS

The foregoing chapters have summarized important findings about ‘pure amnesia’ in humans, and memory dysfunction in normal aging. Although many important aspects of memory dysfunction in these conditions remain to be elucidated, the reader has probably noted the impressive amount of knowledge that already has been gathered. Recently, students of memory have turned their attention to other, frequently occurring conditions were memory dysfunction commonly is observed. Such conditions include Alzheimer’s disease, stroke, and schizophrenia. Researchers have also begun to study experimentally induced memory dysfunction in healthy subjects. The purpose of the present chapter is to describe parts of this work - parts relevant to this dissertation. In particular, memory impairment in connection with Alzheimer’s disease is discussed. Amnesia is the hallmark of dementia. The present author is not aware of any patient suffering from dementia who has not developed memory deficits during the course of illness. At present, the clinical diagnosis of dementia rests upon the objective demonstration of memory dysfunction. Under these circumstances, clearly the understanding of changes taking place in connection with neuro-degenerative disorders is a matter of primary concern. It is not until recently that the tools of experimental, cognitive psychology have been applied to the investigation of memory dysfunction in patients suffering from dementia. The following paragraphs represent an attempt at summarizing some of the findings which recently have been reported.

ALZHEIMER’S DISEASE

Alzheimer’s disease is a relatively common neurological disorder, seldom appearing before the age of 40 in healthy individuals. The disorder is rare in persons younger than 65 - 70 years of age. Therefore, Alzheimer’s disease is primarily a disorder of older people. The prevalence of Alzheimer’s disease is less than one per cent, and might be as rare as three per mille, in populations younger than 65 years of age (Terry, 1976; Wisniewski, 1981). In older populations, the prevalence increases rapidly, to reach a maximum around the beginning of the tenth decade. In populations 90 years and older, the prevalence is probably higher than 25 per cent However, beyond this point, little is known about the prevalence (and incidence) of Alzheimer’s disease. A good guess, though, is that Alzheimer’s disease becomes even more frequent as individuals pass 90 years of age. Histopathologically, the brains of Alzheimer’s disease patients are characterized by several different types of lesions. Two of these lesions are abundant; consequently, they serve as the basis for diagnosis of the illness. It should be noted, though, that histopathological diagnosis of Alzheimer’s disease can only be made at autopsy. Therefore, experimental neuropsychologists have to rely on clinical data for diagnosis. The two most noticeable lesions taking place in Alzheimer’s disease are the occurrence of senile argyrophilic plaques and neurofibrillary tangles. Senile plaques are 10-200 pim large, spherical lesions. The senile plaques consist of a nuclear core that is surrounded by altered neuritic, microglial and astroglial fibers. The major constituent of the core is amyloid. (The term “amyloid” is used to describe “starchlike” aggregates of protein filaments At present, nine different classes of amyloid have been described. They all share some common properties, of which green 44 OTHER FORMS OF MEMORY DYSFUNCTION

birefringence under polarized light subsequent to staining with Congo red, typically can be mentioned.) The amyloid of senile plaques appears to be formed by 60-90 Å filaments, as can be observed on electron microscopy. While the plaque core contains several substances, such as polysaccarides, lipids, and aluminium silicate, a major component is a unique polypeptide, designated ß-protein, or amyloid A4 protein. While the distribution of this peptide is marked in Alzheimer’s disease, the mRNA coding for the precursor of the peptide is present in healthy individuals, as well as in several other mammals than humans. In humans, the gene coding for the amyloid A4 protein precursor is located on chromosome 21. Consequently, the gene is termed the precursor of Alzheimer’s disease A4 amyloid gene, or the PAD gene. Microscopically, the senile plaques are located in the neuropil. Topographically, the senile plaques are localized in the cortical areas, particularly in the posterior association areas and in the frontal lobe. Plaques (as well as neuro-fibrillary tangles) are frequent in layers three and five; curiously enough, they are less often observed in other cortical layers. Abundant plaques are also observed in many areas of the hippocampus and the temporal amygdala. Fewer plaques are seen in the primary sensory and primary motor areas of the cortex. Also, plaques are rare in areas such as cerebellum, hypothalamus, and thalamus. A second hallmark of Alzheimer’s disease is the occurrence of neuro-fibrillary tangles. These are formed by fibrillary material and appear as paired helical filaments, neuro-fibrillary tangles usually appear within cell bodies of pyramidal neurons. Recently, neuro-fibrillary tangles have been demonstrated to stain for ubiquitin and the neuron specific microtubule associated protein tau. In Alzheimer’s disease, neuro-fibrillary tangles are found, first in the hippocampus and later on in cortical areas. None of the two histopathological changes mentioned are entirely specific to Alzheimer’s disease. Senile plaques are found in Kuru (Wisniewski, Bruce, & Fraser, 1975), Creutzfedt-Jacob disease, scrapie, Gerstmann-Sträussler syndrome, progressive supranuclear palsy, in diffuse Lewy body disease, as well as in Down’s syndrome and in normal aging. However, the plaques observed in the slow-virus disorders appears to contain the protease-resistant protein (PrP), rather than amyloid A4 protein. Neuro-fibrillary tangles are found in post-encephalitic parkinsonism, the Parkinson dementia complex of Guam, progressive supranuclear palsy, subacute sclerotic panencephalitis, boxer’s dementia, lead encephalopathy, Down’s syndrome, neural ceroid-lipofuscinosis, Niemann-Pick disease, amyotrophic lateral sclerosis, and normal aging. However, the combination of senile plaques and neuro-fibrillary tangles appears only in Alzheimer’s disease and Down’s syndrome. At present, it remains unclear if these specific co-occurrences can give any clue to the etiology of Alzheimer’s disease. Neuro-fibrillary tangles appear in a number of rare neurological disorders. Some of these disorders have a viral origin (e.g., postencephalitic Parkinsonism), others are due to genetic factors (e.g., neural ceroid-lipofuscinosis). Alzheimer’s disease does not appear to be connected with any of the mechanisms giving rise to the aforementioned disorders. Concerning the conditions where senile plaques are observed, Alzheimer’s disease is not observed following inoculation of the agent causing Kuru (or the related conditions, Creutzfeldt-Jacob disease and scrapie). Rather, Creutzfeldt-Jacob disease or scrapie are seen. Neither is Alzheimer’s disease in itself transmissible. However, the frequency of Alzheimer-like histopathological changes in Down’s syndrome indicate that most Down patients who will reach the middle ages of life, also will develop Alzheimer’s disease. In turn, this worry has also raised the suspicion that Alzheimer’s disease might be linked to alterations with respect to chromosome 21. Recent evidence suggests that a subgroup of Alzheimer’s disease patients actually may evidence an, as of yet unspecified, genetic marker localized on chromosome 21. It is also a notable finding, that the accumulation of amyloid and the subsequent formation of senile plaques precedes the formation of neuro-fibrillary tangles in individuals having Down’s OTHER FORMS OF MEMORY DYSFUNCTION 45 syndrome. In this latter malady, senile plaques first appear in the hippocampus and amygdala, thus giving clues regarding which structures of the central nervous system it is that might be affected early in the course of Alzheimer’s disease. While both senile plaques and neuro-fibrillary tangles are abundant in brain specimens taken from Alzheimer’s disease patients, it is not clear if any of these changes are more important to the diagnosis and etiology of the disease. In general, senile plaques appear to be more sensitive in the diagnosis of Alzheimer’s disease. However, this might stem from methodological differences, rather than neurobiological differences. Besides the occurrence of senile plaques and neuro-fibrillary tangles, the brains of Alzheimer’s disease patients also evidence proliferation of astrocytes, loss of neurons, dyshoric angiopathy, congophilic angiopathy, granulovacuolar degeneration, and white-matter lesions, reminiscent of incomplete infarcts. All these latter alterations appear to take place in some, but far from all Alzheimer’s disease patients. The significance of these latter changes is poorly understood. It is likely, though, that dyshoric and congophilic angiopathy are related to the formation of senile plaques and depositions of amyloid. Granulovacuolar degeneration is related to the appearance of neuro-fibrillary tangles. An interesting question with respect to the course and nature of Alzheimer’s disease, regards the age of the lesions. How long does it take to form senile plaques? It is known that the plaque core contains about 4.57 per cent D-aspartate. Furthermore, it can be estimated that about. 15 per cent D-aspartate is formed per year. Thus, the ratio between these two values (.15 over 4.57) would suggest that it takes about 30 years for a senile plaque to mature (Masters, 1983). Similar estimates have been made, based upon population-based investigations of the presence of amyloid A4 protein in brain samples obtained post mortem (Davies, et al., 1988). These findings seem to indicate two things. First, they indicate that there is an extended subclinical phase in Alzheimer’s disease. Such findings are in keeping with recent reports, describing cognitive impairment in Alzheimer patients some 10 to 15 years prior to the debut of the illness. If the accumulation of amyloid A4 protein forms an integral part of the disease process in Alzheimer’s disease, one is led to wonder what major changes there might be that takes place in the brain some 30 plus years before the onset of illness? The amyloid A4 protein is a membrane bound compound, and believed to be involved in the establishment of cell-to-cell connections. Therefore, one would expect Alzheimer’s disease patients to be deficient with respect to a very fundamental aspect of neuronal plasticity. The exact locus of such a putative deficit has not been delineated, as of yet.

BIOCHEMICAL ABNORMALITIES

Over the years, a large body of data has been gathered regarding the occurrence of biochemical abnormalities in Alzheimer’s disease. Quite naturally, most of this work has emphasized possible alterations with respect to neurotransmitters and neuromodulators. As a consequence of these efforts, a complicated picture has emerged. Alzheimer’s disease patients evidence reductions with respect to “classical” transmitters, such as acetylcholine, serotonin, dopamine, and noradrenaline. Partly due to methodological difficulties, it has been more difficult to demonstrate alterations with respect to more abundant transmitters, such as glutamate, aspartate, GABA, and histamine. With respect to neuropeptides, reductions have been confirmed with respect to somatostatin. Variable results have been obtained regarding anti-diuretic hormone (“vasopressin”) and substance P. Recently, we have obtained results indicative of a reduction regarding delta-sleep inducing peptide in Alzheimer’s disease; a result which, however, awaits further confirmation. Other neuropeptides, such as vasoactive intestinal peptide, cholecystokinin, neurotensin, neuropeptide Y, 46 OTHER FORMS OF MEMORY DYSFUNCTION

and nerve-growth factor, are not altered in Alzheimer’s disease. In fact, certain neuropeptides, such as neuropeptide Y, are highly preserved even at the later stages of the illness. As a consequence of this complicated state of affairs, it is not possible to designate a specific biochemical pattern to Alzheimer’s disease. First, the aforementioned changes are not specific to Alzheimer’s disease. Many of these changes are also seen in other neurodegenerative or psychiatric disorders, as well as in the course of normal aging. Second, there is a considerable variation between Alzheimer’s disease patients with respect to neurotransmitter abnormalities. Reductions with respect to monoamines, and possibly somatostatin, are not obligatory in the disorder. Therefore, it is not possible to link Alzheimer’s disease to any specific neurotransmitter system. It is more likely that the neurotransmitter abnormalities represent symptoms of damage to vulnerable neurons and neural processes. To summarize, then, Alzheimer’s disease is a relatively common form of amyloidosis, which primarily affects people during the later part of the life-span. Although age in itself is a risk-factor for Alzheimer’s disease, the disorder is not a normal form of aging. Rather, Alzheimer’s disease should be regarded as the most significant neurological disorder of old age. A number of neurochemical alterations have been described in Alzheimer’s disease. Furthermore, there is a growing conviction among scientists that genetic factors play a crucial role in the causal mechanism giving rice to Alzheimer’s. Finally, it is possible that Alzheimer’s disease is not one single disorder, but a spectrum of closely related maladies. If, then, Alzheimer’s disease is one of the most common neurological disorders affecting older people, how does it manifest itself, in terms of cognitive neuropsychology? The following paragraphs will deal with this issue.

THE COGNITIVE NEUROPSYCHOLOGY OF ALZHEIMER ’S DISEASE

Alzheimer’s disease has a profound impact upon many modalities of the mind. Therefore, it must be initially stated, that it at present is impossible to describe any relatively simple “core deficit” taking place in Alzheimer’s disease. Furthermore, it must be stressed again that there is an amount of individual variation in Alzheimer’s disease, not the least with respect to neuropsychological signs and symptoms. The fact that patients suffering from Alzheimer’s disease display considerable variation regarding the presentation of the illness should not come as a surprise. This is the rule in every neuropsychological syndrome. It occurs in amnesia, as well as in aphasia or any other broad entity. Recently, writers have highlighted the dangers imminent in lumping together patients with similar symptoms and/or lesions, in particular when one wishes to make inferences about cognitive processes in normals (see, e.g., Caramazza, 1984). One could think of several reasons why this point is important to keep in mind, when one wishes to investigate the cognitive deficits seen in Alzheimer’s disease: (1) There is always individual variation with respect to cognitive abilities, regardless of whether an individual has suffered brain damage or not; (2) With respect to localization, the lesions occurring in Alzheimer’s disease patients always varies to some extent; (3) With respect to involvement of neurotransmitter systems, the lesions occurring in Alzheimer’s disease patients always varies to some extent; (4) With respect to histopathological lesions, the lesions occurring in Alzheimer’s disease patients always varies to some extent; (5) Alzheimer’s disease is superimposed on the process of normal aging —■ irrespective of whether Alzheimer’s disease simply adds to the symptoms produced by advancing age, or interacts with such symptoms, this condition produces variability in Alzheimer’s disease patients; (6) The exact localization of cognitive functions varies between individuals (presumably, this variability concerns topographical localization, as well as the degree of localization, therefore, highly similar lesions can result in somewhat different symptoms); OTHER FORMS OF MEMORY DYSFUNCTION 47

(7) The lesions taking place in Alzheimer’s disease are not stationary — at certain stages of the disorders, results therefore may be impossible to replicate even following relatively short time intervals; (8) Due to specific biochemical abnormalities, and/or motivational changes occurring in Alzheimer’s disease, some variability within subjects is always to be expected. These points should be kept in mind before the discussion continues. This author strongly feels that any serious summary of neuropsychological symptoms seen in Alzheimer’s disease must recognize the heterogeneous manifestation of the disorder.

The realm of Alzheimer* s disease

Typically, Alzheimer’s disease involves derangement of higher cognitive functions. While it was noted that there exist profound individual differences with respect to the clinical manifestation of the disorder, as a rule of the thumb Alzheimer’s disease can be described as following four or five different stages. A first stage of Alzheimer’s disease is a pre-clinical stage. Virtually nothing is known about this stage of the illness. This lack of knowledge extends to the cognitive domain. As was noted earlier, it has been estimated that it takes about thirty years to establish some of the most conspicuous lesions observed in Alzheimer’s disease. Therefore, it is likely that the clinical debut occurs when an individual patient passes a certain threshold. In this respect Alzheimer’s disease is similar to other neuro-degenerative disorders. For example, in Parkinson’s disease, clinical symptoms are not seen until about 80% of the dopaminergic neurons of the substantial nigra are lost. Despite the possibility that extensive damage has to take place before clinical symptoms are seen, a few authors have made the claim that it is possible to describe pre-morbid cognitive markers of Alzheimer’s disease. As part of the Los Angeles twin study, LaRue and Jarvik (1988) administered the WAIS to a large sample of twins. The subjects were monitored from the beginning of the 1960s. A preliminary analysis of the results demonstrated that subjects who had developed clinical signs of dementia also performed inferior to their brothers or sisters up to 15 years prior to the onset of dementia. Interestingly enough, it was not possible to determine any specific neuropsychological profile as regards these subjects. Rather, it was found that they performed inferiorly on a number of tasks, encompassing several cognitive domains. Although the results from this investigation are highly interesting, it must be emphasized that it concerns data from one investigation, specifically. Furthermore, it is possible that the opportunity to study pre-morbid markers of Alzheimer’s disease exists only in samples of twins. In other samples, the pre-morbid signs of the illness might be muddled by individual differences. It should be stated, that there is no good evidence in favour of the hypothesis suggesting that memory dysfunction in the aged in and by itself is a reliable marker of Alzheimer’s disease. In a large prospective investigation, Reisberg, Ferris, DeLeon, and Crook (1985) found no increased incidence of Alzheimer’s disease in older subjects with relatively mild memory dysfunction, in comparison to subjects without symptoms of memory dysfunction. A second stage of Alzheimer’s disease is closely related to the clinical onset of the disorder. At this second stage, memory functions are becoming affected. Other aspects of cognitive functioning are typically not severely affected during the early stages of the illness. This phase of the disorder could most likely be termed “mild” Alzheimer’s disease. Some, but far from all, patients evidence abnormalities on neuropsychological examination during this early phase of the disorder. Therefore, only repeated testing following longer time intervals can aid diagnosis at this stage. As the disease process proceeds, the memory dysfunction is becoming unmistakable. In addition, other cognitive domains are clearly affected. Aphasia, agnosia, visuo-spatial deficits and attentional dysfunction can be evidenced by means of conventional neuropsychological testing 48 OTHER FORMS OF MEMORY DYSFUNCTION procedures. In functional terms, this phase of the illness can be designated the middle phase of Alzheimer’s disease. This stage could be designated a stage of “moderate” cognitive impairment. During this third stage of the disorder, almost every patient suffers from difficulties with respect to every day cognitive activities. Patients are becoming isolated; they have difficulties handling money, performing complex house-hold activities, etc. It is becoming obvious that something is wrong with the patient. Most Alzheimer’s disease patients probably seek help during this stage of illness. A fourth phase of Alzheimer’s disease could be termed a stage of “severe” Alzheimer’s disease. During this stage of the illness, there is a generalized loss of mental functions. Patients have difficulties with many aspects of activities of daily living, and can no longer communicate in a normal way. During this phase of the illness, patients can no longer take part of a routine neuropsychological examination; frequently, only a limited number of tasks can be administered. Later stages of the illness can be termed “very severe” Alzheimer’s disease. Patients need constant monitoring and help, and can usually no longer manage to live at home. Investigations of cognitive functions are extremely difficult to carry out during the terminating stages of Alzheimer’s disease. Neuropsychological assessment during the later stages of Alzheimer’s disease usually must be based upon observation. Several scales and schemes have been constructed to this purpose. Of these scales and schemes, the Global Deterioration Scale (GDS) can be mentioned (Reisberg, Ferris, deLeon, & Crook, 1982). From a broader, clinical perspective, it would appear as if Alzheimer’s disease involves two processes. The first process is somewhat sluggish and slow. It involves the decomposition of cognitive skills involved in communication, language, visuo-spatial abilities and problem solving. This first process might well begin several years before the clinical debut of the illness. As a speculation, we would offer the hypothesis that this process might represent the neuropsychological concomitant to amyloidosis, affecting neocortical sites of the brain. A second process involves damage to limbic structures, most notably the hippocampus and amygdala. This process is faster and more malign in nature. The occurrence of this process usually antedates the clinical onset of Alzheimer’s disease. Dementia, in the light of this hypothesis, might be regarded as the result of the combination of these two aforementioned processes. Having said a few words about the course of Alzheimer’s disease, it is time to discuss findings with respect to aspects of cognitive impairment. In many ways Alzheimer’s disease is one of the best characterized neurological disorders. This might not yet be said about the cognitive neuropsychology of Alzheimer’s disease. However, recent years have witnessed a growing interest in the cognitive alterations occurring in Alzheimer’s disease. Thus, significant contributions have been made, in particular with respect to the understanding of language impairment and memory dysfunction. In general, these findings discussed in the paragraphs to follow, relate to the earlier stages of Alzheimer’s disease. Most experimental studies involve Alzheimer subjects in the “late early” to “moderate” stages of Alzheimer’s disease. These are the phases where amnesia is combined with other cognitive deficits. As already has been pointed out, less is known regarding the earlier stages of Alzheimer’s disease, and the later stages of the illness. In both cases, the lack of knowledge is due to significant methodological problems.

Memory dysfunction

Memory dysfunction is probably the most striking feature of Alzheimer’s disease. Utilizing relatively simple memory tests (such as recall of a ten-word list), the presence and severity of memory dysfunction associated with Alzheimer’s disease can be assessed (e.g., Harris & Dowson, OTHER FORMS OF MEMORY DYSFUNCTION 49

1982). What characterizes the amnesia occurring in this disorder? At present, it is a little bit hard to say. Although investigations regarding memory functions in Alzheimer’s disease are beginning to appear frequently, much of what is happening to memory in Alzheimer’s disease (and other dementias) is poorly understood. This does not apply to every aspect of remembering, though. Working memory (or short-term memory functions) in particular, has been characterized in detail.

SHORT-TERM MEMORY, ATTENTION, AND CONSCIOUS AWARENESS

Is performance in short-term memory tasks impaired in Alzheimer’s disease? Partly, the answer seems to depend upon the specific method employed. One way of investigating short-term memory functions is through inspection of the recency portion of the serial position curve in free recall. Originally invented by Murdock in the beginning of the 1960s, serial position analysis has been employed by enough researchers dealing with Alzheimer’s disease to allow firm conclusions. In Alzheimer’s disease, many investigators have described relatively small deficits with respect to retrieval of recency items (Diesfeldt, 1978; Gibson, 1981; Miller, 1971). In addition, several investigators have been able to compare performance in patients with mild, moderate, and severe Alzheimer’s disease. A majority of these studies show recency effects of normal magnitudes in patients having mild and moderate dementia (Harris & Dowson, 1982; Martin, Brouwers, Cox, & Fedio, 1985; Pepin & Eslinger, 1989; Poitrenaud, Moy, Girousse, Wolmark, & Piette, 1989). In addition, all these studies save one (Martin, Brouwers, Cox, & Fedio, 1985) show attenuated primacy effects in moderately impaired patients. Regarding severe dementia, Harris and Dowson (1982) and Pepin and Eslinger (1989) demonstrated that the recency portion of the serial position curve indeed is impaired at later stages of Alzheimer’s disease. That is, patients with mild to moderate dementia of Alzheimer type evidence recency effects of normal magnitude, whereas patients classified as suffering from “severe” dementia display a flattened serial position curve. The latter finding seems to indicate that short-term memory functions are compromised at later stages of Alzheimer’s disease. However, it is also conceivable that the loss of the recency effect could be due to altered output strategies. Patients with a very severe cognitive handicap may fail to appreciate the utility of a “last in, first out” strategy in single trial free recall tasks. A second measure commonly employed in investigations regarding short-term memory functions, is Tulving and Colotla’s lag measure (Tulving & Colotla, 1970). Similar to the recency portion of the serial position curve, this measure is also based upon free recall of multiple lists. Two investigations have reported modest, but statistically significant deficits with respect to primary memory items (Wilson, Bacon, Fox, & Kaszniak, 1983; Martin, Brouwers, Cox, & Fedio, 1985, experiment 1). In the investigation conducted by Martin et al., the decrement with respect to primary memory items paralleled the decrement with respect to secondary memory items. A third method for the assessment of primary memory functions, is the classical memory span task. In this task, subjects are asked to recall a list of items in serial order. A number of studies have utilized this task in investigations of patients with Alzheimer’s disease, embracing digits, letters, words and blocks as to-be-remembered material. In general, deficits are quite modest with respect to memory span for digits (Corkin, 1982; Kaszniak, Garron, & Fox, 1979; Kopelman, 1985; Morris, 1986, 1987). Indeed, at least two investigations have failed to detect significant differences between (presumably mild) Alzheimer’s disease patients and controls (Martin, et al., 1985; Weingartner, Grafman, Boutelle, Kaye, & Martin, 1983) in this regard. In clinical settings, the digit span task as employed in standard neuropsychological test batteries (such as the WAIS-R), evidently can not discriminate effectively between normal aging and Alzheimer’s disease (Storandt, 50 OTHER FORMS OF MEMORY DYSFUNCTION

Botwinick, Danziger, Berg, & Hughes, 1985). Similar results have been obtained as to the word span task of the Mini-Mental State examination (Vitaliano, Breen, Albert, Russo, & Prinz, 1984). Somewhat more consistent deficits have been observed with respect to the span size regarding letters (Morris, 1984), words (Miller, 1973; Morris, 1984); and Corsi’s visuo-spatial block span task (Cantone, Orsini, Grossi, & De Michele, 1978; Corkin, 1982). The reasons for this possible discrepancy between the span size for digits on the one hand, and most other materials on the other hand, has not yet been clarified. It is possible, though, that some of these latter tasks thrive more upon semantic and spatial knowledge. Such knowledge is, of course, impaired in Alzheimer’s disease. In contrast to the relatively mild to moderate deficits reported with respect to the aforementioned tasks, striking deficits have been found with respect to the Brown-Peterson task (Brown, 1958; Peterson & Peterson, 1959), and tasks resembling this paradigm (e.g., Moss, Albert, Butters, & Payne, 1986). In the Brown-Peterson task, subjects are presented three to-be-remembered items. Following varying delays of interpolated activity (typically, counting backwards by threes from a specified number), the subjects are asked to recall the stimuli. In normal subjects, performance is typically reduced following longer periods of interpolated activity. Corkin (1982) described dramatic impairment in the Brown-Peterson task. This impairment was observed even in mildly affected Alzheimer’s disease patients. Kopelman (1985) compared performance of Alzheimer’s disease patients with performance of patients having amnesia due to alcoholic Korsakoff’s disease. While Korsakoff’s disease patients displayed only mild deficits on the Brown-Peterson task, Alzheimer’s disease patients evidenced marked debilitation. These two investigations combined, suggest that short-term forgetting in the Brown-Peterson task could be relatively specific to Alzheimer’s disease, or at least to dementia. In addition, Moss et al. (1986) described marked recall differences in Alzheimer’s disease subjects at a two-minute recall interval. Furthermore, the deficit was significantly larger in Alzheimer’s disease patients than in patients suffering from Korsakoff’s syndrome and from Huntington’s disease. There is a growing pattern of consensus as regards the performance of Alzheimer patients on short-term memory tasks. In particular, this regards auditory short-term memory tasks; less is known about aspects of visual, motoric, or other kinds of short-term memory functions. Tasks, such as the conventional digit span task of the WAIS/WAIS-R, or immediate free recall of recency items do not evidence striking differences between Alzheimer’s disease subjects and controls. In contrast, tasks requiring effective allocation of attentional resources are invariably difficult for Alzheimer’s disease subjects. Such tasks are dichotic listening tasks, and variations of Baddeley’s working memory paradigm. Theoretically, this data pattern can be accounted for by several modem conceptualizations of the workings of human short-term memory systems. According to modular theories, such as Baddeley’s working memory model (Baddeley, 1986; Baddeley & Hitch, 1974), encapsulated ‘slave systems’ are not severely affected by the disorder. Rather, the locus of the deficit is defective functioning with respect to a superordinate executive system, the central executive (Baddeley, Logie, Bressi, Della Sala, & Spinnler, 1986). According to conceptualizations of short-term memory capacities in terms of controlled vs. automatic processes, Alzheimer’s disease could be characterized as a deficit with respect to controlled or effortfull processes (see, e.g., Jorm, 1986). While this hypothesis is more generalized than the aforementioned hypothesis, it remains extremely difficult to determine the amount of ‘effort’ or ‘control’ that is involved in a particular task. Should this be possible, most of the paradigms invented to address these issues in normals have not been applied to the study of Alzheimer’s disease. Furthermore, it is difficult to ignore the possibility that human short-term memory might be modular in nature. In this regard, models such as the working memory model clearly has an advantage. OTHER FORMS OF MEMORY DYSFUNCTION 51

EPISODIC MEMORY: ENCODING

Alzheimer’s disease is a condition where several intellectual domains are impaired (Miller, 1977). Therefore, it could be expected that the analysis and recoding of to-be-remembered information is a critical aspect of the amnesia seen in Alzheimer’s disease. Several investigations have studied the effects of encoding manipulations in patients suffering from Alzheimer’s disease. Originally, Weingartner and associates (Weingartner, et al., 1981) reported that Alzheimer’s disease subjects were incapable of utilizing semantic features of words to aid remembering. This difficulty took place, regardless of the fact that patients suffering from Korsakoff’s disease could do so. Corkin (1982) investigated the ability to utilize orienting tasks in order to ameliorate memory' performance in Alzheimer’s disease. Three groups of Alzheimer patients (classified as ‘mild’, ‘moderate’, and ‘severe’), healthy controls, and five amnesia patients were tested. The results showed the absence of semantic processing effects upon memory performance in all three groups of Alzheimer’s disease patients. In addition, three of the amnesic patients evidenced no effect of semantic processing. Inspection of the results from the neuropsychological in\estigation revealed that these three patients, in addition to their amnesia, also performed deficiently on certain language tasks (such as the Token Test). Thus, additional language (or semantic memory) deficits may contribute to levels of processing deficits in some amnesics. The generation effect refers to the finding that internally generated (self generated) items often are better remembered than items encoded in a more conventional manner. For instance, the word ‘D_SS__RTATIO_’is better remembered if it is encoded as ‘D_SS_RT ATIOJ rather than ‘DISSERTATICI N ’. Mitchell, Hunt, and Schmitt (1986) compared younger and healthy adults with Alzheimer’s disease patients with respect to the ability to benefit from self generation of words. The results were straightforward, in that the Alzheimer’s disease subjects did not benefit from self generation during study of to-be-remembered words. This pattern contrasted with the performance of healthy young and old subjects. Mitchell et al. suggested that the deficit with respect to semantic memory was responsible for the absence of a generation effect in Alzheimer’s disease. Organization is, as described previously in this dissertation, sometimes an effective mnemonic device. Do Alzheimer’s disease subjects u'iîize organizational skills in order to make encoding more efficient? This question was addressed by Weingartner and associates in two papers (Weingartner, Kaye, Smallberg, Cohen, Ebert, Gillin, & Gold, 1982; Weingartner, Kaye, Smallberg, Ebert, Gillin, & Sitaram, 1981). In the 1981 paper, Weingartner et al. demonstrated that controls were able to memorize more words if the to-be-remembered lists of words were possible to organize into meaningful, semantic clusters. This effect was not observed in demented subjects. In their 1982 article, Weingartner et al. showed that controls learned organizable lists of words more efficiently than non-organizable lists. Even follow ing six trials, Alzheimer’s disease subjects did not show an advantage for organizable learning lists. Weingartner et al. interpreted these findings as reflecting an inability of Alzheimer’s disease patients to use structures stored in semantic memory in order to facilitate new learning. The authors even went so far as to claim that “...patients w ith progressive dementia fail to remember ongoing events because they no longer can access semantic-memory structures that are necessary for encoding information so that it is memorable” (Weingartner, et al.. 1982, pp. 175). Although this hypothesis is very important — it implies that the memory dysfunction seen in Alzheimer’s disease is qualitatively different from other forms of amnesia — the empirical backing is meager. For instance, amnesia can occur as an isolated phenomenon in Alzheimer’s disease, it need not be coupled to semantic memory derangements. Therefore, it is more plausible that amnesia and semantic memory impairment in Alzheimer’s disease represent independent events. 52 OTHER FORMS OF MEMORY DYSFUNCTION

The above-mentioned methods discussed are commonly used to study encoding or acquisition variables. In addition, other investigations, utilizing less conventional methods, also are relevant in this regard. Kopelman (1986) demonstrated that Alzheimer’s disease patients were severely impaired as regards the immediate recall of anomalous sentences. This impairment contrasted with the performance of depressed patients and Korsakoff’s syndrome patients. Despite memory impairments, these latter groups performed normally on the sentence recall task. Kopelman’s results can, of course, be interpreted in several ways. However, the outcome demonstrates that Alzheimer’s disease patients suffer from marked deficits with respect to processing of verbal materials. These deficits probably make an elaborati ve analysis of to-be-remembered information difficult. Utilizing Buschke’s ‘selective reminding paradigm’ (Buschke, 1973; Buschke & Fuld, 1974), Ober, Koss, Friedland, and Delis (1985) compared healthy olds with groups of patients classified as mildly and moderately demented. Hart, Kwentus, Hamer, and Taylor (1987) investigated the memory performance of Alzheimer’s disease subjects, depressed subjects, and healthy controls. In the latter study, both Alzheimer’s and depressed subjects failed to benefit from imagery. In addition, the Alzheimer’s subjects evidenced marked deficits with respect to the consecutive learning of the stimulus material. The writers concluded that this pattern of data was consistent with an encoding deficit in Alzheimer’s disease. The investigation by Ober et al. (1985) also demonstrated an inability of Alzheimer’s disease patients to utilize mental imagery in the selective reminding paradigm. In addition, Alzheimer subjects evidenced marked deficits with respect to long-term learning of to-be-remem bered words. In sum, both these studies involving the selective reminding technique have yielded similar results. The performance of Alzheimer patients was characterized by the absence of long-term learning. In addition, mental imagery did not facilitate the learning of Alzheimer patients. Although this data pattern does not preclude a retrieval deficit, it is likely that encoding problems are responsible for this particular type of deficit. As can be seen, several investigations have demonstrated putative encoding deficits in Alzheimer’s disease subjects. However, there has also been reports yielding results indicative of sparing of encoding processes. Hart, Smith, and Swash (1986b) compared recognition memory for different types of stimuli in Alzheimer’s disease subjects and in older controls. Subjects studied words, ‘abstract stimuli’ (slides of histological preparations and geometric patterns), and faces. Given the presence of encoding deficits in Alzheimer’s disease subjects, it w'ould be predicted that they should not show the normal superiority for non-verbal stimuli, and faces in particular. However, in the study by Hart et al., Alzheimer’s disease patients evidenced relatively intact recognition performance regarding faces. Evidently, then, some contextual manipulations affecting encoding or acquisition of information can be spared in Alzheimer’s disease. A more diréet argument in favour of spared encoding skills was provided by Martin, Brouwers, Cox, and Fedio ( 1985). These investigators reported that Alzheimer’s disease patients were able to utilize semantic encoding to the same extent as healthy older controls, despite gross performance differences between groups. Obviously, the finding of a normal sensitivity to a ‘levels-of-processing’ manipulation is difficult to reconcile with an encoding account of memory dysfunction in Alzheimer’s disease. There are several problems with the explanation of Alzheimer’s disease in terms of encoding deficits. First, groups of Alzheimer’s disease patients are compared to patients suffering from of amnesia or dysmnesia related to other etiologies. Thus, Alzheimer’s disease patients are often compared to patients suffering from Korsakoff’s disease, Huntington’s disease, and healthy, older individuals. All these populations have commonly been observed to suffer disproportionately in memory tasks where encoding operations are taxed. OTHER FORMS OF MEMORY DYSFUNCTION 53

STORAGE AND CONSOLIDATION

The amnesia observed in Alzheimer’s disease is very severe. Therefore, one would expect that a rapid forgetting of information occurs in Alzheimer’s disease. Although a mere handful of investigations have addressed this issue, available evidence suggest that Alzheimer’s disease patients forget information at a rate similar to healthy older subjects (and younger subjects, for that matter). Kopelman (1985) tested recognition memory performance after 10 minutes, 24 hours, and 1 week. In this study, the performance of Alzheimer’s disease subjects was compared to the performance of Korsakoff’s syndrome patients, and controls. Corkin, Growdon, Nissen, Huff, Freed, & Sagar (1984) evaluated recognition performance after 10 minutes, 24 hours, and 72 hours. Two similar experiments were discussed by Freed, Corkin, Growdon, and Nissen (1989). In all these investigations, the rate of forgetting over longer time intervals was identical in all groups examined. However, in the studies by Corkin et al. (1984), and Freed et al. (1989), Alzheimer’s disease subjects evidenced more rapid forgetting over the first 24 hours. At 72 hours, this difference had vanished. These investigations show clearly that Alzheimer’s disease patients do not evidence abnormal rates of forgetting. At least this holds for longer time intervals. As regards shorter time intervals, where Alzheimer’s disease patients at times evidently evidence accelerated rate of forgetting, Freed et al. (1989) reported that this phenomenon was observed in a subgroup of patients. These patients evidenced signs of marked attentional dysfunction, according to clinical, neuropsychological measures. Alternatively, the recognition performance of dementia subjects could reflect increased arousal or ‘test anxiety’ during acquisition. It has repeatedly been demonstrated that emotional stimuli are more difficult to remember at shorter time intervals. Following longer time intervals, this ‘impairment’ disappears (Bradley & Baddeley, 1990; Kleinsmith & Kaplan, 1963, 1964; Parkin, Lewinsohn, & Folkard, 1982). At any rate, forgetting is spared in Alzheimer’s disease; the subtle deficits that can be demonstrated occasionally contrast drastically against the severity of the amnesia of Alzheimer’s disease. Interestingly enough, the slope of forgetting curves is sometimes used as an indicator of storage capacity. If something is wrong with the storage system (so that information can’t be consolidated and stored over longer time intervals), it would be expected that forgetting should be faster. Since the rate of forgetting seems to be normal in Alzheimer’s disease, it could be argued that storage capacity and/or consolidation mechanisms are spared. In turn, this raises hopes that the amnesia seen in Alzheimer’s disease can be alleviated by means of psychological and pharmacological interventions.

Retrieva l

How are retrieval processes affected by Alzheimer’s disease? To this date, the evidence is conflicting. However, a relatively large number of studies have documented retrieval deficits. Therefore, it is possible that retrieval deficits contribute significantly to the amnesia seen in Alzheimer’s disease. Several investigations of Alzheimer’s disease patients have described difficulties in using retrieval cues in order to facilitate remembering. Davis and Mumford (1974) found Alzheimer’s disease subjects to be unable to utilize semantic retrieval cues to boost memory performance. However, when to-be-remembered words were cued with the initial letter at time of testing, Alzheimer’s disease subjects evidenced gains. Although Davis and Mumford interpreted this finding as indicative of an encoding deficit in Alzheimer’s disease, most researchers would 54 OTHER FORMS OF MEMORY DYSFUNCTION

probably consider Davis and Mumford’s data as reflecting retrieval dysfunction. (See also the discussion in the section on implicit memory below.) Similar to the findings of Davis and Mumford, Diesfeldt (1984) found that Alzheimer’s disease patients could not use semantic retrieval cues to improve recall of words. However, since Diesfeldt used lists of different lengths for patients and controls, the results are difficult to understand. A somewhat different type of evidence suggestive of retrieval dysfunction, comes from investigations highlighting intrusion errors in the recall protocols of demented patients. Fuld, Katzman, Davies, and Terry (1982) reported that intrusion errors were more frequent in Alzheimer’s disease patients than in controls. Furthermore, the number of intrusions was negatively correlated to markers of cholinergic activity. As regards recognition tasks, an investigation conducted by Branconnier, Cole, Spera, and DeVitt ( 1982) merits special attention. These authors asked non-demented older subjects and Alzheimer’s disease patients to memorize words. Subsequent memory testing involved two procedures, free recall and recognition. Interestingly enough, the recognition test permitted a more rigorous discrimination between groups than did the free recall test. Obviously, a straightforward interpretation of these findings would be that Alzheimer’s disease patients suffer from a retrieval deficit. Since the Alzheimer’s disease patients suffer from a retrieval deficit, the provision of copy cues is relatively ineffective. The recognition memory deficit applies not only to word lists, but also to pictures (Moss, et al., 1986), faces (Ferris, Crook, Clark, McCarthy, & Rae, 1980; Flicker, Ferris, Crook, & Bartus, 1990; Moss, et al., 1986; Wilson, Kaszniak, Bacon, Fox, & Kelly, 1982), and SFT:s (unpublished observations). The above mentioned investigations have demonstrated retrieval dysfunction in Alzheimer’s disease. However, there are also a number of investigations that have demonstrated Alzheimer patients to be able to use retrieval cues as proficiently as healthy subjects. Martin et al. (1985) tested provided both free and cued recall test following various orienting tasks. In addition to the finding of spared encoding capabilities (see above), Martin et al. also found that Alzheimer’s disease subjects were able to use retrieval cues as efficiently as controls. However, the conclusion that retrieval processes therefore were spared in these patients, has been questioned. Morris and Kopelman (1986) pointed out that the controls performed at ceiling when semantically encoded words were tested with retrieval cues. Thus, it is still possible that demented subjects are particularly at stake when it comes to retrieval of semantically ‘rich’ information. Buschke and associates have provided some indirect evidence in favour of the position that Alzheimer’s disease patients can use retrieval information efficiently (Grober, Buschke, Crystal, Bang, & Dresner, 1988; Buschke, 1984). In these studies, Alzheimer’s disease subjects usually were able to reproduce pictorial items from memory when semantic cues were provided, but not when no cues were given. Indeed, Buschke and associates have utilized this phenomenon in an ingenious way in order to improve the quality of clinical memory assessment (Grober, et al., 1988). Thus, free recall of pictorial stimuli did discriminate between healthy controls and Alzheimer’s disease patients more effectively than did cued recall. Tuokko and Crockett (1S39) also utilized Buschke’s cued recall paradigm in order to elucidate the relation between memory capacity and every day clinical symptoms. Although the purpose of the investigation conducted by Tuokko and Crockett was not to study effects of various retrieval manipulations upon remembering, the writers found that the ability to utilize retrieval cues w'as impaired in patients w ith more severe psychosocial functioning. Since patients w ith less marked impairment w ith respect to psychosocial functioning performed poorly on a free recall task, it w as concluded that retrieval operations are at stake in early-stage dementia. Using a somewhat unusual method, Winocur, Moscovitch, and Witherspoon (1987) asked healthy controls, alcoholic controls, Korsakoff patients, and institution living older people to learn a OTHER FORMS OF MEMORY DYSFUNCTION 55 list of paired-associates under two experimental conditions. The PA lists could be studied, either in a conventional laboratory, or in a room with distinctive contextual features. Although no diagnosis of Alzheimer’s disease was confirmed, it is possible that several of the older, non-alcoholic subjects residing in institutions suffered from an early stage dementia. The results demonstrated that both Korsakoff’s disease patients and institutionalized older subjects were more sensitive to the presence of distinct contextual cues. That is, memory impairment was marked when subjects were tested under conventional laboratory settings. The memory impaired subjects could presumably utilize the additional retrieval information provided by a distinct testing environment. Quite recently, Partridge, Knight, and Feehan (1990) described a situation where Alzheimer’s disease subjects were able to use retrieval cues with the same proficiency as controls. In this experiment, subjects studied words under semantic encoding conditions — the subjects were asked to construct a sentence for each to-be-remembered word. At time of testing, subjects were sometimes asked to recall the stimuli. At other occasions, the subjects were cued with the first three letters of the stimulus words. When retrieval cues were provided at time of testing, subjects were at times asked to recall the previously studied words. At other times, subjects were given an indirect or implicit memory task. The subjects were asked to complete the cues with the first word that came to mind. (The latter part of the experiment was of main interest to Partridge et al., and will be discussed more in detail below. However, the experiment also contributes to the knowledge about effects of retrieval manipulation in dementia.) Although controls remembered more words than patients under both free- and cued recall conditions, the difference was markedly attenuated when recall was aided by retrieval cues. Under free recall testing conditions, the difference between groups amounted to 49 per cent. Under cued recall testing conditions, the difference was reduced to 27 per cent. Unfortunately, Partridge et al. did not report any statistical analysis of this putative group by type of test interaction. However, at least the results show that Alzheimer’s disease patients were not less helped by retrieval cues than controls. In conclusion, it can be seen, that there is no clear-cut evidence favoring retrieval operations as the locus of the deficit in Alzheimer’s disease. Rather, it appears as if there is a continuum, involving retrieval skills increasingly at later stages of the illness. However, few systematic attempts have been addressing this issue. Similar to the understanding of encoding mechanisms in Alzheimer’s disease, conclusions have to rely upon comparisons between scattered experiments conducted in varying settings.

ENCODING-RETRIEVAL INTERACTIONS

Whereas an impressing number of researchers have studied the effects of encoding and retrieval variables in isolation, surprisingly few investigations have emphasized encoding-re trie vai interactions. Given the popularity of the encoding specificity hypothesis (Tulving, 1983), this is a draw-back. However, a few investigations have addressed this topic. Diesfeldt (1984) presented lists of categorizable words to controls and to patients having dementia of varying severity. The demented patients were unable to organize the material spontaneously in order to support memory performance. In addition, the patients were deficient with respect to the use of retrieval cues. However, when organization during encoding was combined with retrieval support at time of testing, the demented patients improved significantly. Unfortunately, Diesfeldt used study lists of varying length for controls and patients. Thus, although the patients improved as much as controls when the retrieval cues were compatible with the encoding activity, this finding regarded proportional data. Therefore, Diesfeldt’s finding concerning lists of organizable words awaits replication. 56 OTHER FORMS OF MEMORY DYSFUNCTION

More recently, Granholm and Butters (1988) conducted an encoding-retrieval experiment modelled after the original experiments by Thompson and Tulving (1970) and Tulving and Thompson (1973). Granholm and Butter’s experiments comprised four groups of subjects: Alzheimer’s disease patients, Huntington’s disease patients, older controls, and middle-aged controls. The subjects recalled paired-associates under five different experimental conditions. Under two of these conditions, the relation between cue and target was identical at study and testing. There could be a strong pre-experimental association between the items (e.g., ‘night - DAY’) or a weak association (e.g., ‘sun - DAY’). Under two other conditions, the relation between cue and target was different from study to test. However, at study as well as test, items still were weakly and strongly associated. The fifth condition was a condition of free recall. The main finding from research on younger, normal subjects, is that the compatibility between encoding and retrieval is as important to successful retrieval as is the pre-experimental association between cue and target (Thomson & Tulving, 1970; Tulving & Thomson, 1973). This finding is of course of extreme importance, since it demonstrates that memory performance cannot be predicted from the knowledge of the strength of association between cue and target. Thus, memory is something rather different from the repeated association of stimuli, i.e., the central dictum of learning theory. In the study by Granholm and Butters (1988), controls and Huntington’s disease subjects performed quite similarly (although Huntington’s subjects recalled fewer words over all). These groups of subjects all evidenced the highest memory performance when strong relations between cue and target were present at both study and test. The worst performance was seen in the condition where a strong association between cue and target was present at encoding, and a weak relation was present at time of testing. The other conditions fell in between these extremes. Interestingly enough, the Alzheimer subjects evidenced a different pattern. The main difference was observed in the condition where weak relations between cues and targets were present at time of study and time of testing. In contrast to the other groups, the Alzheimer’s disease recalled fewer words in this condition than in the other conditions of the experiment. Just as the other groups in the experiment, the Alzheimer subjects recalled most words when strong relations between cue and target where present at both study and test. (In fact, the differences between groups were slight when strongly associated cues were provided at time of testing.) Granholm and Butters (1988) also noted that the performance of the Alzheimer subjects was qualitatively similar to the performance of Korsakoff’s syndrome subjects, as reported by Cermak, Uhly, and Reale (1980). Since Alzheimer’s disease patients, as well as Korsakoff’s syndrome patients suffer from central deficits as to the neurotransmitter acetylcholine, Granholm and Butters suggested that the abnormal performance in the encoding-retrieval paradigm is linked to the cholinergic deficit. The experiment by Granholm and Butters indicates two things. First, the result suggests that the ability to make the retrieval information congruent with the information stored in the memory trace, is severely defective in Alzheimer’s disease. Furthermore, the result indicates that Alzheimer’s disease patients can utilize the semantic relation between items to support remembering. In contrast to the investigation by Granholm and Butters (1988), Martin et al. (1985) did not find support for the usefulness of explanations in terms of encoding, retrieval, or encoding-retrieval interactions in the understanding of memory dysfunction in Alzheimer’s disease. Despite large quantitative differences between demented patients and controls, the qualitative pattern was identical in Alzheimer’s disease subjects and in controls. That is, the Alzheimer subjects were helped by the orienting tasks employed by Martin et al. (see previous discussion). The magnitude of this improvement was similar in patients and controls. Similarly, Alzheimer’s disease subjects and healthy control subjects were aided by the provision of retrieval cues. The magnitude of this effect was, again, comparable in both intact and demented subjects. OTHER FORMS OF MEMORY DYSFUNCTION 57

The studies by Granholm and Butters are extremely important, since there are few investigations that have undertaken to investigate encoding-retrieval interactions in patients with dementia. Most studies have dealt with encoding or retrieval processes, specifically. However, it is well known that encoding activities and retrieval cues interact. There are, of course, no a priori reason why individuals suffering from memory dysfunction should be different. On the contrary, one attractive explanation of amnesia highlights the possible importance of encoding-retrieval interactions. Amnesic patients possibly suffer from amnesia because these persons are incapable of combining the products of encoding activities (and perhaps storage processes) with retrieval information. Under these circumstances, to refrain from investigating encoding processes without varying the demands at retrieval, can only serve to confuse matters. While recognizing the importance of encoding-retrieval interactions in research on amnesia, it should be clear that there are but a few investigations addressing these issues. Concerning Alzheimer’s disease, this author has located two studies that explicitly bear upon this issue. It is probably unnecessary to point out that two experiments is far to little to allow for firm conclusions.

PERFORMANCE IN INDIRECT MEMORY TASKS

Just as several other domains discussed in relation to Alzheimer’s disease, performance in implicit memory tasks has resulted in a complex picture. Some investigators have documented priming effects of normal magnitude, other have described an impairment with respect to priming and implicit memory in Alzheimer’s disease. Moscovitch, Winocur, and McLachlan ( 1986) investigated recognition performance and reading time in three different experiments. The former measure was used as a measure of explicit memory; the latter measure was used to denote implicit memory. In all experiments, Alzheimer’s disease patients, as well as institutionalized subjects, evidenced impaired performance with respect to the recognition memory tasks. However, at the same time, the same subjects evidenced marked facilitation as to the reading time measure. That is, the fact that an Alzheimer’s disease or memory impaired subject studied a particular item, facilitated subsequent reading — but not recognition — of the same item. The study by Moscovitch, Winocur, and McLachlan (1986) replicated an earlier, small scale investigation by Moscovitch (1982a). In this latter study, Moscovitch found three Alzheimer’s disease subjects and one amnesic subject to perform normally regarding reading of inverted text. In addition, subjects were also unimpaired with respect to direct priming in a lexical decision task. Corkin (1982) utilized the Gollin Incomplete-Pictures Test (Gollin, 1960; see also Warrington & Weiskrantz, 1968) in order to investigate ‘perceptual learning’. In this task, subjects are shown perceptually degraded line drawings. The drawings can be presented at five levels of fragmentation, and a savings index is commonly employed in order to depict learning from one trial (or block of trials) to the next. In the experiment conducted by Corkin, patients classified as having ‘mild’ dementia of the Alzheimer type evidenced significant savings, after a retention interval of 1 h, as well as after 24 h. However, patients having moderate and severe dementia did not evidence statistically significant savings. (However, the group of patients having Alzheimer’s disease of moderate severity did display savings at the 1 h testing interval. In nominal terms, the magnitude of this effect was larger than the statistically significant savings effect of mild dementia patients.) Implicit tasks involving word stem completion (e.g. Graf, Squire, & Mandler, 1984) have evidenced impairments among Alzheimer’s disease patients (Shimamura, Salmon, Squire & Butters, 1987; Heindel, Salmon, Shults, Walicke, & Butters, 1989). A similar outcome has been reported with respect to conventional free association tasks (Brandt, Spencer, McSorley & Folstein, 1988; Salmon, Shimamura, Butters, & Smith, 1988). Since several studies have documented 58 OTHER FORMS OF MEMORY DYSFUNCTION preserved performance in amnesics, using the aforementioned paradigms, these investigations may highlight a cognitive deficit unique to Alzheimer’s disease. While the investigations on implicit memory using word stem completion and free association tasks seem to indicate a deficit relatively unique to Alzheimer’s disease, other investigations have reported conflicting results. A somewhat earlier investigation by Davis and Mumford (1984) described a strong dissociation between performance on explicit memory tasks (free recall and cued recall) on the one hand, and an implicit memory task on the other. In this latter task, subjects were cued with the first letter of stimulus words. Alzheimer’s disease subjects recalled many items under this latter condition. Although Davis and Mumford interpreted this outcome as indicative of an encoding deficit, nowadays most writers would probably treat the result as an example of spared implicit memory functions in Alzheimer’s disease. Recently, Partridge et al. (1990) found patients with Alzheimer’s disease to evidence normal priming effects in a word stem completion task. This result was obtained, although the Alzheimer subjects evidenced gross memory dysfunction on all explicit memory tasks employed. Partridge et al. suggested that the preserv ation of the priming effect in their demented subjects could be related to how to-be-remembered words were encoded. Partridge et al. used a sentence generation task at time of study. That is, subjects were not only asked to memorize words. For each word presented, the subjects were also asked to construct a sentence embodying the particular word. Thus, in the study by Partridge et al., a reliable priming effect in demented patients was observed following semantic encoding of information. It is possible, therefore, that elaborative encoding is needed under many circumstances in order for priming effects to take place in dementia Clearly, this possibility should be put to a direct test Regarding semantic priming, Ober and Shenaut ( 1988) described deficits in Alzheimer’s disease. Employing a lexical-decision task, Ober and Shenaut found Alzheimer subjects to show no priming ensuing semantic activation. That is, a target word, such as ‘nurse’, was not easier to process if it was presented immediately after a related word, such as ‘doctor’. This lack of priming effects was not global, however. Alzheimer’s disease subjects evidenced intact repetition priming (e.g., the word ‘nurse’ was presented several times), as well as phonological priming (e.g. the word ‘nurse’ had been primed by the word ‘purse’). The foregoing paragraphs have documented a complex picture as regards implicit memory. It should be understood, that several investigations embracing indirect tests of memory in Alzheimer’s disease, suffer from serious shortcomings. Thus, investigators have not provided appropriate baseline measures (e.g., Davis & Mumford, 1984). That is, the seemingly normal performance by Alzheimer’s disease subjects could be due guessing, rather than implicit activation of target items. Furthermore, very few, if any, researchers have compared Alzheimer’s disease subjects and other amnesic subjects on indirect memory tasks in the very same experiment! That is, the absence of priming effects in Alzheimer’s disease patients could be present in other amnesics as well. Since there is no such thing as a ‘standard’ priming test, this latter point is extremely important. In fact, the investigations comparing Alzheimer’s with other amnesics, evidenced intact priming (Moscovitch, 1982a; Moscovitch, Winocur, & McLachlan, 1986). In most tasks, patients with Alzheimer’s disease have, at times, been demonstrated a normal performance, as well as deficits. It is possible that Alzheimer’s disease patients are impaired in tasks which are related to episodic memory performance — such as the word stem completion task. However, the memory impairment seen in Alzheimer’s disease is not confined to these instances. Therefore, it is possible that differences with respect to the severity of the dementia and differences with respect to task demands contribute to the complex picture. While cognizant of all these short-comings, still an intelligible pattern emerges concerning priming effects and the phenomena of implicit memory7 in dementia. More specifically, three things OTHER FORMS OF MEMORY DYSFUNCTION 59

seem to have been uncovered about implicit memory in Alzheimer’s disease and other neurodegenerative disorders. First, the phenomena of implicit memory seem to be characterized by a fairly large amount of modularity. In Alzheimer’s disease, deficits with respect to implicit memory are observed in tasks like word-stem completion and the free association task. It can be assumed that language skills in general and semantic skills in particular, are important to the successful execution of these tasks. In Alzheimer’s disease, marked deficits are seen as to the cortical areas crucial to semantic memory, i.e., the posterior association cortex of the parietal lobe. Consequently, Alzheimer subjects evidence deficits on many semantic and conceptual tasks (e.g., Grober, Buschke, Kawas, & Fuld, 1985; Martin & Fedio, 1983; Rissenberg & Glanzer, 1987; Warrington, 1975; see also Nebes, 1989 for an excellent review). In neurodegenerative disorders different from Alzheimer’s disease, other regions of the brain are affected. For example, in Huntington’s disease, basal ganglia structures, such as the Caudate nucleus, are severely affected. In Parkinson’s disease, the substantia nigra is primary target of the illness. As a consequence of these lesions, patients suffering from Parkinson’s disease and (in particular) Huntington’s disease, evidence other deficits with respect to implicit memory than those described in connection with Alzheimer’s disease. Thus, Huntington’s disease patients and patients suffering from parkinson dementia2 evidence impairment with respect to motoric tasks that can be primed in Alzheimer’s disease and in the amnesic syndrome. The apparent dissociation between the localization of lesion and type of implicit memory impairment is most interesting. Unlike episodic memory, these data suggest that there is nothing such as one single neural locus for implicit memory. Rather, implicit memory, and phenomena such as priming, might be intimately coupled to those modules of the central nervous system that carries out a certain type of processing. In this regard, implicit memory is different from episodic memory. In the latter case, optimal function is dependent upon the integrity of the hippocampus, and possibly certain temporal lobe structures as well. The second and third aspects of implicit memory in Alzheimer’s disease are related to semantic memory. Second, testing Alzheimer’s disease subjects in verbal priming tasks, priming effects might be stronger if the target information was semantically encoded (Partridge, Knight, & Feehan, 1990). This is not an effect specific for implicit memory tasks. A similar situation exists with respect to retrieval manipulations — Alzheimer’s disease subjects can utilize semantic retrieval cues if the subjects have been engaged in elaborative encoding at time of study (Buschke, 1984b). At present, it is not at all clear why Alzheimer’s disease subjects would evidence priming effects subsequent to elaborative encoding and otherwise not. One possible answer is that priming is the result of activation of information in semantic memory. Due to parietal lobe damage, such activation might be difficult in Alzheimer’s disease. However, other explanations are possible. The difficulties as to implicit activation of information could be due to damage to more automatized processes. Elaborative encoding therefore might substitute the information that no longer is spontaneously encoded. Third, the opposite seems to be the case as regards activation of information in implicit tasks: the less semantic activation needed, the larger the probability is that information is primed. Semantic priming is a good example at hand. When semantic priming is assessed by means of word pronunciation tasks, subjects with Alzheimer’s disease evidence normal priming effects (Hartman, 1987; Nebes, Martin, & Horn, 1984). When semantic priming is studied by means of the lexical-decision task, the results are much more varying. Thus, Ober and Shenaut (1988) found no

^The term ‘parkinson dementia’ refers to the fact that a portion of patients having Parkinson’s disease, in addition to their motoric impairment, also become demented. Most likely, the parkinson dementia is not a unitary disorder. Some parkinson dementia patients suffer from Parkinson’s disease. In other patients, Alzheimer’s disease is superimposed upon Parkinson’s disease. In yet another group, neuropathological features of Alzheimer’s disease (senile plaques) are combined with neuropathological features of Parkinson’s disease (Lewy bodies). 60 OTHER FORMS OF MEMORY DYSFUNCTION evidence of semantic priming in Alzheimer patients. In contrast, Nebes, Boiler, and Holland (1986) found Alzheimer’s disease subjects to display normal facilitation following semantic priming. Although this discrepancy can be explained in terms of technical differences between the experiments (Nebes, 1989), it is still possible that the lexical-decision task puts higher demands upon lexical access than does the word pronunciation task (Ober & Shenaut, 1988). The possibility that priming effects are linked to the integrity of semantic memory is important to the understanding of neuropsychological deficits taking place in Alzheimer’s disease. However, this hypothesis is also important with respect to the understanding of the organization of human memory. Although many theorists have suggested that many implicit memory functions are based upon a unique memory system, the data from Alzheimer patients suggest that the implicit activation of information is an aspect of semantic memory. For example, it is possible that information must be overleamed before it can be implicitly primed. When the products of such overlearning begin to disappear, as in the full-blown dementia syndrome, then performance in indirect memory tasks suffers. It should be noted, that it follows from this summary, that the investigation of implicit memory in patients having Alzheimer’s disease of varying severity, is a very important question. Similarly, patients with different neurodegenerative disorders should be compared on implicit c memory tasks. To this date, such comparisons have been made between Alzheimer subjects, Korsakoff’s syndrome patients, Parkinson’s disease patients, and Huntington’s disease subjects. It would also be of vital interest to investigate implicit memory in age-associated memory impairment, stroke, the adult hydrocephalus syndrome, and other neurodegenerative disorders relatively common in older people.

TRANSFER AND LEARNING

In studies on Alzheimer’s disease, a limited number of investigations have been concerned with phenomena related to learning. However, certain, relatively simple motor acts can be acquired in Alzheimer’s disease (Eslinger & Damasio, 1986; Heindel, et al., 1989). In addition, this aspect of preserved learning contrast to the performance of patients suffering from Huntington’s disease and Parkinson’s disease. The latter groups of patients evidence marked difficulties concerning the learning of motoric skills (Heindel, et al., 1989). Thus, the preservation of motor learning skills is not obligatory in the dementias. According to Heindel, Salmon, and Butters (1989), the putamen could be a part of the brain central to acquisition of motor skills (including procedural learning). Since the putamen is relatively preserved in many Alzheimer patients, it would be expected that motoric learning also should be possible in Alzheimer’s. The preservation of skills related to leisure activities were investigated by Schacter (1983). Schacter described a passionated golf player, who eventually fell victim of Alzheimer’s disease. Despite the severity of the disorder, this patient could play golf, adjust to changes taking place during a game, and carry out a conversation relevant to the game. The sparing of certain learning skills may not be confined to motor skills, however. Little, Volans, Hemsley, & Levy (1986) tested Alzheimer patients repeatedly over six month intervals. Subjects were assessed by means of a conventional paired-associate learning task. Little et al. found that the patients performed better on repeated paired associates than on items altered between sessions. These ‘savings’ occurred over intervals of two months. It would be important to know to what extent the patients actually remembered the information, or if savings were the result of acquisition of a verbal skill. OTHER FORMS OF MEMORY DYSFUNCTION 61

CORRELATIONS BETWEEN DIFFERENT MEMORY DEFICITS

A central theoretical question with respect to the memory deficits seen in Alzheimer’s disease, regards the relation between the various cognitive deficits occurring in this condition. For instance, if there is a deficit in Alzheimer’s disease as to the central executive (e.g., Baddclev, Logie, Bressi, Della Sala, & Spinnler, 1986), then this deficit should influence and impair other aspects of remembering. For example, encoding operations should be affected by such a deficit. Originally, a somewhat related idea was suggested by Miller (1971, 1973). Based on the contemporary structural models of memory (e.g., Atkinson & Shiffrin, 1968), Miller suggested that demented patients suffer from difficulties at early stages of processing. In turn, these deficits would result in a disruption as to the transfer of information from a temporary- state to a permanent state. From an other angle, it is possible that Alzheimer patients suffer from a retrieval deficit. Should this be the case, it is difficult to ignore the possibility that such a putative retrieval deficit also would affect encoding operations. That is, the efficacy of encoding operations thrives, among other things, upon the activation of schemes relevant to a given situation. If such “retrieval” is damaged, it is likely that encoding operations would suffer. These remarks illustrate the difficulty in designating the locus of the deficit in Alzheimer’s disease. The problem is not diminished by the possibility that two or more of these putative deficits could coexist in Alzheimer’s disease. As regards Alzheimer’s disease, many important questions are still unanswered. For example, it would be extremely important to now multiple deficits observed in this disorder interact. Take the following example to clarify this point. As can be read from the preceding paragraphs, there are some evidence in favour of a retrieval deficit in Alzheimer’s disease. Alzheimer’s subjects probably have more pronounced difficulties when it comes to utilizing semantic retrieval cues (e.g.., Davis & Mumford, 1984; Diesfeldt, 1984; Weingartner, et al., 1982). Alzheimer patients also have difficulties regarding repeated learning — they evidence a ‘flattened retrieval curve’ (Luria, 1980). This latter finding is evident in tasks, such as the selective reminding paradigm (e.g., Fuld, 1980).

SUMMARY

This section discussed many investigations regarding episodic memory in Alzheimer’s disease. Four conclusions can be drawn. First, many aspects of primary memory are preserved in Alzheimer’s disease. Second, performance in indirect memory tasks is most likely preserved when the Alzheimer subjects are engaged in semantic encoding during study. Third, motor learning is relatively preserved in Alzheimer’s. Fourth, Alzheimer’s disease patients can utilize retrieval cues and the products of elaborative encoding to attenuate the amnesia observed in this disorder. However, this amelioration seems to occur in a somew hat inconsistent manner. Some researchers report gross deficits in Alzheimer’s disease subjects, other experimenters describe a qualitative pattern similar to that observed in healthy older subjects. The causes behind these variations have not been identified.

HUNTINGTON’S DISEASE

Huntington’s disease is a relatively uncommon hereditary neurological disorder, affecting 1 individual in 10000. Its main characteristic is the appearance of motor impairment, and in particular choreatic movements at later stages of the illness. The motor impairment is brought about as a consequence of damage to the caudate nucleus and other basal ganglia structures. At a relatively 62 OTHER FORMS OF MEMORY DYSFUNCTION early stage of the illness, the disease process also engages cortical structures connected to the neostriatum; most noteably frontal cortical sites. Huntington’s disease is inherited according to an autosomal dominant mode of transmission. The biochemical abnormalities occurring in Huntington’s disease have not been worked out in detail. However, it appears that neurons that stain for GABA-like immunoactivity show a selective vulnerability in the disease. Also, cholinergic and glutaminergic neurotransmission might be altered, contributing to the neurological abnormalities seen in the illness. Basic information regarding the neurobiology of Huntington’s disease can be obtained, e.g. from the following sources: Graveland, Williams, and DiFiglia (1985); Greenamyre, Penny, Young, D ’Amato, Hicks, and Shoulson ( 1985); P. L. McGeer and E.G. McGccr (1976); Sanberg and Coyle ( 1984); Sax, O’Donnell, Butters, Menzer, Montgomery, and Kayne (1983); and Spokes (1980). In addition to a movement disorder, cognitive changes also take place in Huntington’s disease, although these latter changes might appear somewhat milder than the cognitive changes seen in Alzheimer’s disease. Nelson Butters and his associates have shown that patients with Huntington’s disease have marked deficits with respect to performance on episodic memory tasks and non-verbal intelligence tasks. In contrast, performance on verbal intelligence tasks (semantic memory tasks) is preserved in the disorder (Butters, 1984). This latter position has, however, recently been challenged by Caine, Bamford, Schiffer, Shoulson, & Levy (1986). In general, patients suffering from Huntington’s disease often evidence memory dysfunction at a relatively early stage of the illness. At later stages, when the neurodegenerative process affects the frontal cortex, fundamental cognitive processes are affected, such as concept formation abilities and planning abilities. During the end stage of the disorder, a more global dementia syndrome is seen (Josiassen, Curry, & Mancali, 1983; Sax, O’Donnell, Butters, Menzer, Montgomery', and Kayne, 1983). Despite the stability of this general neuropsychological pattern, it has been more difficult to characterize the memory' deficit occurring in Huntington's disease in detail. A number ofinitial studies suggested that Huntington’s disease patients suffer from an encoding deficit. Thus, Huntington’s disease patients evidenced no recall superiority of highly imageable words over low-imagery words (Weingartner, Caine, & Ebert, 1979), failed to evidence positive effects of a semantic orienting task (Biber, Butters, Rosen, Gerstmann, & Mattis, 1981), were not able to boost memory performance given longer time for rehearsal (Butters & Grady, 1977) or when intertrial intervals were made longer (Butters, Tarlow, Cermak, & Sax, 1976). However, at the same time Huntington’s disease patients suffer from marked retrograde amnesia (Albert, Butters, & Brandt, 1981a; 1981b); and evidence strong and disproportionate benefits when retrieval is supported by means of retrieval cues (Butters, Wolfe, Granholm, & Martone, 1986; Butters, Wolfe, Martone, Granholm, & Cermak, 1985; Caine, Hunt, Weingartner, & Ebert, 1978; Martone, Butters, Payne, Becker, & Sax, 1984). These latter findings suggest that retrieval operations might suffer in Huntington’s disease patients. This suspicion also gains support from the demonstration that providing a story' to a picture-background association improved remembering in Huntington’s disease patients, but not in other types of amnesia (Butters, Albert, Sax, Miliotis, Nagode, & Sterste, 1983). That is, some encoding processes might be preserved in Huntington’s disease. In sum, the bulk of results coming from Butters’ laboratory seems to suggest that retrieval deficits account for a substantial part of the memory disorder observed in patients suffering from Huntington’s disease. Interestingly enough, it has also been proposed that these retrieval deficits also apply to performance in semantic memory' tasks; and that this pattern differentiates Huntington’s disease patients from patients suffering from Alzheimer’s disease and Korsakoff’s syndrome (Butters, Granholm, Salmon, Grant, & Wolfe, 1987). Since the neostriatum, and to a large extent also the association areas of the frontal cortex are damaged in Huntington’s disease, the implication is of course that these regions of the brain might be important to retrieval processes. The implications of this position are, of course, fundamental: neostriatal-cortical connections might OTHER FORMS OF MEMORY DYSFUNCTION 63 be damaged in several significant neurological and neuropsychiatrie disorders others than Huntington’s disease; e.g., schizophrenia. In addition, the neostriatum is highly vulnerable to the effects of normal aging (see other section of this text). Several authors have made the claim that retrieval processes are particularly vulnerable to the effects of aging (Burke & Light, 1981; Nilsson, Bäckman, & Karlsson, 1989; present investigation). Therefore, a putative retrieval disorder in aging might be due to age-associated alterations of basal ganglia structures and their cortical connections.

CEREBRO-VASCULAR DISORDERS

Although the consequences of disruption with respect to the circulation of blood and nutritients are one of the most common causes of neuropsychological dysfunction, relatively little is known about the consequences as regards memory functions. A solid body of knowledge has been gathered with respect to language skills and affective changes; which is reflected in most modem textbooks of neuropsychology. This state of affairs has no direct counterpart in the literature on learning and memory. In particular, this is true as to experimental investigations of patients suffering from intra-cranial infarcts or hemorrhages. Since cerebrovascular disorders frequently produces memory dysfunction, and at times an amnesic syndrome (e.g., Benson, Marsden, & Meadows, 1974; Hirst, 1982; Horenstein, Chamberlain, & Conomy, 1967; Linquist & Norlen, 1966; Medina, Rubino, & Ross, 1974; Mills & Swanson, 1978; Norlen & Olivercrona, 1952), it is likely that investigations of such changes will be considered more important in the years to come. This belief is further supported by the fact that regions of the brain which are related to learning and memory, are vulnerable to the effects of disturbances regarding blood flow (e.g., Brierley, 1972). Clinical investigations regarding consequences of vascular lesions as to memory performance, have concentrated on the role of the thalamus in remembering. Following the description of amnesia subsequent to traumatic damage to the dorsal medial nucleus of the thalamus (Squire & Moore, 1979), several authors have described amnesia following bilateral thalamic damage (Graff-Radford, Damasio, Yamada, Eslinger, & Damasio, 1985; von Cramon, Hebei, & Schuri, 1985; Winocur, Oxbury, Agnetti, & Davis, 1984). Although claims have been made that this form of amnesia (involving the thalamus) is different from the amnesia engaging hippocampus and other temporal lobe structures (e.g., Squire, 1982a), at present this claim lacks empirical support.

CHAPTER FIVE: SUMMARY OF CURRENT INVESTIGATION

The experiments reported about in this dissertation are founded on a relatively simple idea: remembering depends on several things. It is acknowledged that remembering depends on the integrity of neural circuitry of the brain, and, in particular, the integrity of the inferior temporal lobe. However, the integrity of these areas of the brain is not sufficient to bring about memory performance. Under many circumstances, whatever is done with the to-be-remembered information in terms of cognitive processing, is what makes the difference. Memory is the result of perceptual analysis, understanding, and several other mental processes. As to the memory circuits of the brain, it is not known if these circuits primarily function to integrate the results of various types of processing, or if they add new qualities to the stored information. Termed differently, the first hypothesis is that there exist different input routes to the establishment of memory traces, engrams; engrams that can result in a subsequent experience of recollection. 64 CURRENT INVESTIGATION

Actually, there is also a second assumption behind the studies discussed in this thesis. The second assumption is simply that amnesia is a matter of degree. That is, memory dysfunction is a quantitative concept, rather than a qualitative concept. This second assumption is probably not at all controversial. Patients with a memory dysfunction can show more or less of this decline. There are a number of studies showing that this is the case, and the critical reader is referred to any textbook dealing with amnesia (e.g., Squire, 1987). When these two ideas are combined, it is possible to assume that persons who suffer from memory dysfunction - presumably of an organic origin - should be able to combine their biological capacity with the products of processing in order to give rise to some kind of memory. The five first investigations comprising this thesis constitute different approaches to this problem. The sixth investigation deals with some issues that are developed from the other investigations. To repeat the main argument again: when persons remember things, remembering depend upon several things. We do not know that much about what these ‘things’ are. Most memory scientist would probably agree that memory performance depends upon the biological capacity of the brain to encode, store, retrieve, and reconstruct information, and upon the effectiveness of the rememberer to process information. The person who tries to learn or recall something, is not merely another word for the brain’s capacity with respect to encoding, storage, and retrieval. Irrespective of whether you have a ‘good’ brain or a ‘bad’ brain, it does matter what you do when you try to remember things. Researchers have emphasized metamemory and processing of information as important regarding the rememberer’s own activity upon memory performance. Metamemory is about the subject’s own knowledge of what he knows or does not know. Metamemory also refers to the subject’s own ability to respond to the obvious fact that some tasks are difficult, and other tasks are easy. That is, sometimes one has to take the time needed to encode the information one wants to be able to retrieve at a later occasion. In other situations, one can rest back and just register the information, in a more passive fashion, because you already know a lot about the topic or the situation. Regarding the direct effects of processing upon remembering, a good deal of memory research already exists. Virtually all contemporary theories of human memory mention the direct effects of the rememberer’s own activity on memory. All influential theories focus on this issue. The levels of processing framework (Craik & Lockhart, 1972) describe how elaboration influences memory performance. The transfer appropriate processing (Bransford, McCarrell, Franks, & Nitsch, 1977) and the transfer appropriate procedures (Roediger, Weldon, & Challis, 1989) explanations both emphasize the interplay between activities during acquisition and activities at the time of utilization of knowledge. The encoding specificity hypothesis (Tulving & Thomson, 1973) clarifies how the circumstances surrounding retrieval of information interacts with stored information to yield recollective experience. Since this dissertation is concerned with memory dysfunction, it should be stated that brain lesions can exert direct effects upon a person’s ability to be an effective rememberer, irrespective of whether the brain’s biological storage capacity has been damaged or not. The most typical example in this regard is probably patients suffering from the alcoholic Korsakoff syndrome. These patients do not only acquire amnesia. They also show signs of frontal lobe damage. The latter deficit makes it more difficult for these patients to carry out elaborative encoding of to-be-remembered information (see, e.g., Butters & Cermak, 1980). In addition to deficits in elaborative processing, many Korsakoff patients are also confabulating; that is, describing events that have taken place in the imagination of the patient only. This inability in separating real memories from fantasies, makes it difficult for the patient to know when he should spend more time processing a certain task. CURRENT INVESTIGATION 65

A third factor of critical importance to remembering, is the environment (or context) of the rememberer. Although environmental factors have not been emphasized in the psychology of memory to the same extent as in research on perception, it is unlikely that all information related to remembering is stored in the central nervous system. The influence of external factors on memory is most obvious regarding retrieval or reconstructive processes. Nowadays, it is textbook knowledge that availability and accessibility of information can be separated (Tulving & Fearlstone, 1966). Under most circumstances, knowledge can be reactivated, given appropriate retrieval cues. This is true for amnesic patients as well. However, it still not known if retrieval cues are more or less effective than in controls (Mayes & Meudell, 1981). Whereas important knowledge with respect to contextual influences upon retrieval processes has been acquired, less is known about encoding, storage, and consolidation processes in this , regard. For storage and consolidation processes, few, if any, variables have been described as influencing these processes (Weingartner & Parker, 1984). As to encoding processes, it is well known that semantic or elaborative encoding is crucial, but very little is known about the situational cues that elicit such processing. Thus, an individual’s memory7 performance is determined by: (a) the capacity of the central nervous system, (b) the activities of the rememberer, and (c) the physical situation. In addition, the activities of the rememberer can be understood in metacognitive terms, and in terms of the immediate effects of processing upon memory. The aim of this dissertation is not to determine which of these influences that gives rise to amnesia. It is the strong belief of this author that such an enterprise would be doomed to fail. The reason is simple. All of these factors contribute to amnesia, although the exact influence can vary. The reason for this variation is not yet understood. The four comers of Jenkin’s tetrahedron model (Bransford, 1979; Jenkins, 1978) illustrate this state of affairs. For example, in a certain amnesia patient, the damage inflicted to the innate storage and retrieval systems of the brain are perhaps so severe, that the remaining factors are relatively unimportant. A typical example is most likely the patient with a circumscribed hippocampal lesion. In an other amnesia patient, a loss of attentional capacity, in combination with loss of insight into the disability, would prevent elaborative encoding under many circumstances. A patient suffering from Pick’s disease is a typical example of this. On the basis of what has been said so far, it should be understood that the three critical factors mentioned interact. In each particular case there is a certain contribution from each factor. However, on the basis of the current state of knowledge in the field it is yet too early to seek to determine the exact contribution for each factor in a single case of amnesia. The scope of any research endeavour has to be more limited. The basic aim of the present thesis is to demonstrate that there are situations in which one principal determinant to remembering can substitute other determinants.3 In the current studies, the emphasis is placed upon factors related to the nature of learning activities and reconstructive activities. There are several ways to study the influence of such activities on remembering, and some of these have been discussed in previous sections. In the present thesis, special importance is given to the self-initiated activity on behalf of the rememberer. The fact is, that most methods that can be used to study the effects of processing upon remembering, involve some kind of self-initiated activity. Therefore, four of the six studies involve

3An interesting question in this context, is whether the different determinants of remembering yield identical results, or if the end product is different. Unfortunately, this is yet another question that is not addressed in this investigation. However, it is possible that memories that are not determined by the brain’s storage and retrieval systems do not result in the same type of recollective experience as memories that have been stored efficiently. This can be observed when subjects are asked to indicate whether they ‘remember’ or ‘know’ if a particular item has been presented previously (Gardiner, 1988). It is possible that the memory circuits of the brain are responsible for an item being identified as being remembered. 66 CURRENT INVESTIGATION self-generation of to-be-remembered items. The two remaining experiments deal with problems that are related to the possibly beneficial effects of self-initiated activity on behalf of the rememberer upon memory performance. One factor which in particular has been suspected to restrain a person’s abilities to engage in active processing, is the limitation of attentional capacity. One study explores this possibility through the variation of materials and methods of testing. One study employs a dual task paradigm. Although the current thesis is not restricted to the study of memory dysfunction occurring in normal aging, it is a matter of course that age-related memory dysfunction deserves special attention when memory impairment is discussed. After all, age-associated memory impairment affects a significant number of people. In this dissertation, age-associated memory impairment receives special attention in two ways. First, in four of the six studies comprising this thesis, two groups ofelderly subjects were employed. The younger of these groups were between 70 and 80 years of age. This group is usually called ‘young-olds’. The older (‘old-old’) of these groups were more than 80 years old. In addition to these groups of elderly subjects, younger controls were employed. The reason behind the inclusion of two groups of elderly, healthy subjects was as follows. Although the term ‘age-associated memory impairment’ frequently is used to account for age-related changes as to memory' function, it is not common to make distinctions between groups of elderly subjects. How ever, differences betw een younger and older elderly subjects might be as large as differences between younger elderly subjects and young adults. For example, with respect to memory performance, a 70 year old subject may be more similar to a 25 year old subject than a 90 year old subject. Furthermore, theoretical accounts of age-related memory decline seldom differentiate between elderly subjects. However, it is not at all certain that memory dysfunction taking place during the seventh decade of life can be explained in the same way as memory dysfunction appearing during the tenth decade of life. Since very little is known about differences between ‘younger’ and ‘older’ elderly subjects, an effort was made to provide some initial data as to this topic. The second way in which age-associated memory impairment is considered, regards Alzheimer’s disease. Most authorities nowadays make a sharp distinction between age-associated memory impairment and Alzheimer’s disease. This is so, because milder memory problems in elderly people usually do not lead to manifest dementia. As indicated in a previous chapter, Alzheimer’s disease is rather seen as a distinct neurological disorder (or, perhaps, several neurological disorders), w hich primarily affects elderly individuals. However, still Alzheimer’s disease is clinically related to age-associated cognitive alterations. In both conditions, memory dysfunction is usually the most obvious characteristic. Many elderly persons, being aware of memory problems, fear that their memory problems are early signs of Alzheimer’s disease. In addition to clinical similarities between age-associated memory' impairment and Alzheimer’s disease, biological similarities exist as well. There are neuropathological similarities (e.g., the occurrence of senile plaques) and neurochemical similarities (cholinergic and monoaminergic reductions). The first two papers of this thesis demonstrate that contextual support at study improves remembering in healthy elderly adults, as w'ell as in patients suffering from Alzheimer’s disease. The third paper utilizes this knowledge in an attempt to treat a central neuropeptidergic defect knowrn to take place in Alzheimer’s disease. The remaining three papers deal w ith possible theoretical explanations of memory dysfunction in general, and age-associated memory impairment in particular. Experiment 4 utilizes an encoding-retrieval paradigm to study whether elderly subjects are equally sensitive to the convergence betw een the results of encoding operations and retrieval cues provided at time of testing. In particular, the interest is directed towards the question of whether a similar pattern is CURRENT INVESTIGATION 67 observed in ‘younger’ and ‘older’ elderly subjects. In Experiment 5, a similar question is asked. This time, however, a paradigm is employed which allows for the separation between explicit and implicit aspects of the process of remembering. In addition, two groups of younger subjects with experimentally induced amnesia arc included into the investigation. Experiment 6, finally, investigates the contribution of the ability to divide attention to memory performance in young, ‘young-old’, and ‘old-old’ subjects.

EXPERIMENT 1 : GENERATION

An interesting phenomenon is the generation effect. This effect is the finding that people remember a material more effectively if the to-be-remembered material somehow is constructed by the remember. The general idea behind the first experiment of this study was to investigate if elderly subjects can alleviate their memory' dysfunction through self-generation of the to-be-remem bered material. Since the generation effect is an important phenomenon in the psychology of memory', it would certainly be interesting to know whether the generation effect is preserved in older adults. How ev er, there were also more specific considerations behind this experiment. It is known since long that young children evidence marked generation effects. In a series of now’ classical investigations regarding memory' functions in children, the Russian psychologist Smirnov (Smirnov & Zinchenko, 1979) studied the effects of self-generation in a play-like paradigm. When 5 year old children w ere asked to memorize objects, their performance fell below’ the performance of 10 year old children. However, Smirnov and associates also allowed their subjects to ‘encode’ the to-be-remembered objects while playing grocery store. When the younger children were allowed to memorize the objects in a play-like environment, the performance of the 5 year olds approached that of the older children. Furthermore, the generation effect has been investigated in amnesic patients. Milner (1982) reported that patients suffering from amnesia due to temporal lobe damage, were able to improve memory' performance subsequent to self-generation of to-be-remem bered words. Thus, if young children and amnesic patients are able to utilize self-generation in order to promote memory performance, shouldn’t healthy, elderly subjects also be able to do so? After all, the degree of amnesia is most likely less conspicuous in elderly adults than in the other groups investigated. The second reason for studying the generation effect in old age is related directly to one possible mechanism behind memory dysfunction in human aging. It is common knowledge that older adults suffer from attentional deficit. As a consequence of such limitations, encoding operations might be suffering (e.g., Craik, 1977b). At the same time as older subjects hav e attentional derangements, they perform normally on many semantic memory tasks (see, e.g., Kausler, 1982, 1989). Therefore, at least in theory', the possibility exists that elderly subjects can use their intact semantic memory skills to make up for attentional dysfunction. It is possible that self generation of to-be-remembered words could w ork in this way. The fact that the rememberer constructs the stimulus items, serv es to foster encoding. The argument can even be taken one step further. It is conceivable that self generation not only facilitates encoding processes in general. One of the main issues as regard memory dysfunction in human aging concerns the possibility that the elderly person does not use optimal encoding strategies. The reason for his deficit may be difficulties in the initiation of effective encoding strategies, rather than an inability per se to conduct effective encoding. One interesting aspect of self generation, is the possibility that self generation provides elderly subjects with effectiv e attentional means. Attention is allocated to the analysis of the to-be-remembered information, since the subject is engaged in a form of well-known problem solving activity. The control of attention is 68 CURRENT INVESTIGATION accomplished by means of the rememberer being engaged in a cognitive task. This might be favorable for elderly subjects, since the mere instruction to memorize in a more effective manner simply might not be enough (see also Experiment 3 below).

METHOD

Three groups of adults (young, ‘young-old’, and ‘old-old’) participated in this experiment. Each group comprised 10 subjects. The younger subjects (mean age 21 years) were paid volunteers; the elderly subjects (73 and 82 year old, respectively) were recruited from an ongoing, longitudinal study regarding medical and psychological health in old age. Through this study it was ascertained that the elderly subjects were not suffering from Alzheimer’s disease, stroke, or any other neurological illness that seriously could bias the results. The memory task employed in this experiment was an incidental memory task. The subjects were individually tested in a quiet room. They were told that one aim of the investigation was to study changes with respect to language during the adult age span. The incidental learning task on behalf of the subjects was to provide familiarity ratings of to-be-remembered words. For each subject, 20 medium frequency words (50 to 100 per million) were presented. Half of the material was presented as words; the other half was presented as word fragments. The word fragments were constructed through removal of two letters. Furthermore, care was taken to ensure that only one solution existed for each fragment. The words/word fragments were presented one at a time. The subjects were instructed to construct words from the fragments, to read each word loud, and then report the rating to the experimenter. Each word/fragment remained visible for 15 s. After a particular word was removed from sight, the subject provided the familiarity rating for that particular word. Five s. were allowed for the rating. The procedure was repeated until the whole list of words had been presented. After presentation of the list of w'ords, the subjects were asked to recall as many words as possible. Five min. w'ere allowed for free recall.

RESULTS AND DISCUSSION

Younger adults recalled an equal number of words and word fragments (59% vs. 58%). Older subjects, and in particular the group of ‘old-old’ subjects, tended to recall more word fragments than words. The group of ‘young-old’ subjects remembered 29% of words, and 34% of w'ord fragments. The group of ‘old-old’ subjects recalled 15% of words, and 30% of word fragments. Planned comparisons, utilizing the Bonferroni correction, revealed that the difference between word fragments and words w'as statistically significant for the group of ‘old-old’ subjects. The outcome of the present experiment revealed two things. First, age differences take place, not only when older adults are compared to younger adults. Age differences also exist when comparisons are made across a relatively narrow range in old age: in the present context, between 82 year old subjects and between 73 year old subjects (i.e., nine years). This is an important finding. It suggests, that caution should be taken, when findings regarding one group of older subjects are applied to another (i.e., younger or older) group of older subjects. The second finding of this experiment indicates that younger and older adults are differentially sensitive to the encoding of to-be-remembered information in a context of self-activity. This differential sensitivity takes place, despite the existence of gross average differences between groups. CURRENT INVESTIGATION 69

In sum, the outcome of Experiment 1 is straightforward Under certain circumstances, older subjects can overcome some of their memory deficits, given that they are engaged in some form of self-activity (or problem-solving activity) during acquisition of to-be-remembered information.

EXPERIMENT 2: MEMORY IMPROVEMENT IN ALZHEIMER’S DISEASE

Although a number of investigations have investigated memory performance in healthy, older adults, and in amnesic patients, far less is known regarding memory deficiencies occurring in Alzheimer’s disease. In particular, little is known about ways to improve memory performance in subjects suffering from dementia. Is it possible to improve memory’ performance in patients suffering from Alzheimer’s disease? The question is important, at least for two reasons. First, a number of investigations have documented an insensitivity to contextual support in Alzheimer’s disease (see previous chapter). Second, Alzheimer subjects suffer from several cognitive deficiencies that could limit the ability to benefit from contextual support. For instance, Alzheimer’s disease patients have language deficiencies, ranging from anomia to global aphasia. Alzheimer patients suffer from attentional deficits, as well as visuo-spatial dysfunction, affective changes and psychiatric problems (such as anxiety disorders). All these neuropsychological deficits could make it more difficult for Alzheimer patients to benefit from various forms of contextual support. The latter usually thrives upon relatively advanced conceptual skills (e.g., semantic orienting tasks) or visuo-spatial abilities (e.g., visual imagery). The basic notion behind Experiment 2 was to investigate if an encoding task, presumably bypassing some cognitive deficits taking place in Alzheimer’s disease, also will bring about memory improvement. Motor coding was selected, and this for a number of reasons. (1) Motor coding has been demonstrated to improve naming in Alzheimer’s (a naming deficit is usually seen in Alzheimer patients). (2) Many cerebral areas involved in motoric skills are most likely relatively preserved in Alzheimer’s disease. (3). Motor enactment might help to control allocation of attentional resources. For example, when a person is asked to ‘turn off the radio’, the engagement in carrying out the task also helps to maintain the action. However, when a similar sentence is presented, it is left to the subject to contemplate the meaning of the sentence. The motor coding task employed, was Cohen’s Subject Performed Task (SPT) paradigm. In this task, the to-be-remembered material consists of lists of short actions. Examples include actions, such as ‘open the envelope’ and ‘bounce the ball’. The subjects in this type of experiment are presented one such command at a time, together with the appropriate object. After a list of actions has been administered, the subject is asked to recall or recognize the items in the list. Usually, memory’ for SPT:s is compared to memory for material that lacks the motoric component. Experiment 2 comprised three groups of patients suffering from Alzheimer’s disease. Just as it was shown in Experiment 1 that healthy older subjects responded differently, despite relatively small age differences, it was expected that differences between Alzheimer patients also could be demonstrated. In particular, it was suspected that the severity of dementia might attenuate the ability to benefit from contextual support. Thus, patients with a less severe form of dementia could be expected to benefit more from motor coding than severely demented patients.

METHOD

Five groups of subjects were included. Two groups were ‘young-old’ and ‘old-old’ healthy controls. The criteria for inclusion of controls were the same as in Experiment 1. The former control group was 73 years old, the latter 82 years old. Three groups of patients suffering from 70 CURRENT INVESTIGATION

Alzheimer’s disease were employed. The diagnosis of Alzheimer’s disease was based upon international research criteria for probable Alzheimer’s disease, as discussed by McKhann, et al. (1984). Once a subject was given the clinical diagnosis of Alzheimer’s disease, he was placed in one of three Alzheimer groups: mild, moderate, and severe dementia. Clinical staging was based upon performance on a brief neuropsychological test, the Mini-Mental State Examiner)', MMSE (Folstcin, Folstein, & McHugh, 1976). Subjects scoring above 20 on the MMSE were designated ‘mild’ Alzheimer’s disease; subjects scoring between 15 and 20 were designated ‘moderate’ Alzheimer’s disease; and subjects who fell below 15 on the MMSE were regarded as suffering from ‘severe’ Alzheimer’s disease at the time of examination.4 The to-be-remembered material consisted of 25 action commands. The stimuli were drawn from five semantic categories, e.g., clothes and kitchen utensils. In the motor coding condition of the experiment, the 25 action commands were presented to the subjects, one at a time. Simultaneous with the presentation of a particular action command, the subject was provided the appropriate object (e.g., a ball when the to-be-remembered item was ‘bounce the ball’). Ten s. was allowed for each action. When the presentation was finished, subjects were asked to recall as many items as possible. Five minutes was allowed for free recall. After five minutes had elapsed, a self-paced cued recall test was administered. In this test, the names of the semantic categories that comprised the to-be-remembered material were provided. Again, the subjects were asked to recall as many items as possible. To allow for evaluation of the effect of motor coding, a verbal experimental condition was introduced. In this condition, subjects read sentences depicting the same nominal information as was used in the SPT condition. However, in the verbal condition of the experiment, no motor enactment of the commands was requested. The design in this experiment was a between subjects design. Thus, subjects from each of the five groups included in the study were randomly allocated to either the verbal condition or the SPT condition.

RESULTS AND DISCUSSION

The main finding of this study was that motor coding improved memory performance in patients suffering from Alzheimer’s disease. In particular, this improvement was observed in patients with ‘mild’ dementia. Although the magnitude of the difference between recall of SPT:s and sentences was larger in controls than in patients, this interaction effect did not reach statistical significance. It can be concluded that motor coding does help demented patients to memorize information in a more effective way, although the results are not unequivocal as regards the question of whether motor coding is entirely spared at early stages of Alzheimer’s disease. The result of Experiment 2 could also be taken as an indication of a more general principle. Given the opportunity of efficient encoding, even patients suffering from severe amnesia can improve memory performance. This fact lends support to the basic contention put forward here, namely, that deficiencies of the memory systems of the brain can be alleviated by means of more effective utilization of the very same memory systems.

^The maximum possible score on the MMSE is 30; a score below 27 is often regarded as indicative of a possible cognitive abnormality; a score below 24 indicates a clinical dementia syndrome. CURRENT INVESTIGATION 71

EXPERIMENT 3: SOMATOSTATIN TREATMENT IN ALZHEIMER’S DISEASE

One of the most intriguing findings concerning Alzheimer’s disease, regards the neurochemical abnormalities observed in this disorder. With respect to the classical neurotransmitters, acetylcholine is severely depleted in regions of Alzheimer brains, at least when nervous tissue is examined post mortem. Other ‘classical’ transmitters, such as dopamine and serotonin are also depleted, at least at later stages of Alzheimer’s disease, and in some Alzheimer patients. However, neurochemical alterations in Alzheimer’s disease may not be confined to deficits regarding the ‘classical’ neurotransmitters. First, Alzheimer patients exhibit deficits as to the neuropeptide Somatotrophin-Release Inhibiting Factor, SRIF (somatostatin). The depletion of SRIF is surprisingly selective; in Alzheimer’s disease no other neuropeptide deficiency has been documented in a consistent manner. Second, deficits as to excitatory amino acids (L-glutamate and possibly L-aspartate) have been demonstrated to take place in Alzheimer’s disease. These latter changes can be of profound interest. Glutamate is believed to be the most important neurotransmitter of the corticocortical association fibers of the brain’s association areas. Treatment of cognitive dysfunction in Alzheimer’s disease has mainly been concerned with correction of depletion of the classical transmitters in general, and acetylcholine in particular. Since these treatment regimens have been unsuccessful, treatment strategies directed toward other neurochemical deficits are becoming increasingly important. To this aim, the purpose of this study was to investigate effects of treatment usinga synthetic SRIF analogue in patients with Alzheimer’s disease. There are three reasons for investigating effects of SRIF treatment in Alzheimer’s disease. First, as was indicated above, SRIF is depleted in brains of Alzheimer patients. This simple fact is in and by itself enough to warrant the investigation of SRIF treatment in Alzheimer’s disease. Second, little is known about the function of SRIF in the central nervous system. Since SRIF is depleted in patients who evidence amnesia, it is possible that SRIF subserves a function as to memory. However, patients suffering from Alzheimer’s disease do also evidence other neuropsychological deficits, in addition to amnesia. Thus, it is possible that the deficit with respect to SRIF is related to language dysfunction, or visuo-spatial deficits, rather than memory dysfunction, specifically. The third reason to investigate SRIF in Alzheimer’s disease, regards putative biological functions of this peptide. SRIF has been indicated in cytoprotection. Furthermore, SRIF subserves important functions in the regulation of glucose metabolism. Both these functions may be causally related to Alzheimer’s disease. Therefore, damage to SRIF bearing neurons might be an early event in the chain of events that produces Alzheimer’s disease. The purpose of Experiment 3 was to investigate the effects of SRIF treatment in patients suffering from Alzheimer’s disease. Given the considerations discussed above, the investigation involved determination of language skills, visuo-spatial skills, and metabolic capacity, in addition to study of memory capacity. SRIF treatment was implemented, utilizing the synthetic SRIF analogue SMS 201-995 (‘Sandostatin’). Each patient was administered the equivalent of 75 mg SMS 201-995 iv. The compound was given under two different conditions: with or without the administration of 150 g glucose. In addition, two placebo conditions were utilized. Subjects were given either 150 g glucose (without the simultaneous administration of the SRIF analogue), or saline. The reason behind the administration of glucose, was the fact that SRIF, as well as SMS 201-995, has profound effects upon glucose metabolism. Thus, due to an inhibition of insulin and glucagon, at least in theory, SMS 201-995 could cause a relative hypoglycemia when given without the simultaneous administration of glucose. 72 CURRENT INVESTIGATION

Functions related to memory capacity were assessed by means of an SPT task, related to the task used in Experiment 2. Similar to Experiment 2, the SPT task embraced measures of free and cued recall. The SFT task was preferred to more conventional paradigms because it allows for control of processing of to-be-remembered items. This property is particularly important when memory function is tested in Alzheimer’s disease. Alzheimer subjects may at times fail to remember because of attentional lapses and test anxiety. A second reason behind the choice of the SPT task was that theoretically relevant questions can be investigated, using this paradigm. Such theoretically interesting questions can be raised, even in patients suffering from severe amnesia and other cognitive deficits. Thus, in the current investigation, retrieval demands were varied, by means of comparisons between free and cued recall of SPT:s. If SMS 201-995 improves memory performance in Alzheimer’s disease patients, then it is possible that this improvement more easily can be described, if retrieval demands are varied. More specifically, measures involving retrieval support could, at least in theory, be more sensitive to drug effects. The memory task employed in Experiment 3 did also allow for separation of influences from primary and secondary memory, respectively. This is an important issue, since pharmacological effects upon memory performance could be related to performance in secondary memory tasks.

METHOD

The investigation embodied eight subjects, suffering from Alzheimer’s disease. All subjects were at a relatively early stage of the disorder. All subjects met research criteria for ‘probable Alzheimer’s disease’, according to the NINCDS-ADRAS research criteria. In addition, all subjects had been followed for at least six month before the investigation. Histopathological confirmation of Alzheimer’s disease has been obtained in one subject. The design of the experiment was a within-group design. Thus, all subjects were given SMS 201-995. Administration of this compound was combined with administration of glucose to yield four different experimental conditions: SMS 201-995, SMS 201-995 in combination with glucose; glucose without the concomitant administration of SMS 201-995; and saline. The order between treatments was counterbalanced according to a Latin square design. All treatments were administered in a double-blind fashion. Each subject was seen on six consecutive days. One day one, a subject was installed at the geriatric psychiatry ward, where the experiment was conducted. On day two, routine medical, neurological, and neuropsychological investigations were carried out. The experiment was then conducted on days three to six. To evaluate treatment effects upon cognitive functions, four different cognitive tasks were employed. Each task existed of sixteen versions. Episodic memory was assessed by means of the SPT paradigm. In the present version of the task, the subjects studied one list of 10 action commands (e.g. ”Lift the glass”, "Take on the glove”). Each action command was read out by the experimenter at 10 second intervals. Simultaneously with each presentation, a real life object was provided. The task on behalf of the subject was to carry out, and to memorize each action. Immediately following the presentation of each list, 90 seconds was allowed for free recall. Following free recall testing, a self-paced cued recall test was administered. Here, the action verb of each command was provided as retrieval cue (e.g., "Lift the...", "Take on the..,"), and the subject was asked to remember the whole item. Semantic memory (i.e., general knowledge about the world) performance was assessed by means of a category retrieval task. Twenty-four general categories were selected from Swedish category norms (Nilsson, 1973), and eight additional categories were added ad lib by the investigators. In the category retrieval task, the experimenter read out a category name, and the CURRENT INVESTIGATION 73 subject was asked to name as many instances of this category as possible during 60 seconds. During each testing session, two categories were presented, one at a time. Short-term memory and attention were measured by means of the conventional digit-span task of the Wechsler Adult Intelligence Scale (Wechsler, 1955). Two digit-strings were presented during each testing session. The number of digits presented varied with baseline performance, i.e., was equal to the digit span of each subject. Visuo-spatial abilities were assessed by means of a figure copying task. This test was modeled after Muramato, Sugishita, and Ando (1984). In the figure copying task, the subject was presented with a geometric pattern, a pencil and a rubber gum, and was asked to copy the figure. This task was self-paced but the subjects were encouraged to make another attempt if they failed this test. Other investigations. During each testing session, self-ratings (by means of a visual analog scale) of mood and affect were obtained. In addition, before each testing session, blood samples were obtained. These blood samples were later analyzed for the contents of glucose, insulin, glucagon, GH, SRIF, and SMS 201-995. In other to detect possible side-effects of treatments, blood-pressure and pulse were monitored before each testing session and through the whole day of treatment. During each day of clinical testing, four testing sessions took place. All sessions included cognitive and medical examinations, as described above. The order between tests was always as follows: Recording of pulse and blood-pressure, blood sampling, episodic memory, semantic memory, digit span, visuo-spatial task, self-ratings of mood and alertness. The first testing session (0 min.) established base-line values/performance during each day. This testing session always occurred between 8.00 to 8.30 in the morning. The infusion started immediately after this session. A second testing (90 min.) occurred 90 (±5) minutes after the onset of infusions. A third examination (180 min.) was undertaken 180 (±5) minutes following the onset of infusion. This session followed immediately after the termination of the infusion. A fourth, and final testing session (360 min.) was carried out 360 (+10) minutes after baseline (and, thus, 180 minutes after the termination of infusion).

RESULTS AND DISCUSSION

Experiment 3 demonstrates three things. First, SMS 201-995 affects peripheral metabolism of glucose in Alzheimer’s disease subjects. These effects show that the synthetic SRIF analogue employed really is pharmacologically active. Second, and most importantly, the study failed to evidence beneficial effects of treatment utilizing a SRIF analogue, SMS 201-995. This failure took place, although SMS 201-995 attenuated the increase of blood glucose following the administration of glucose; and despite the fact that the subjects included in the study evidenced depletion of cerebrospinal fluid SRIF-like immunoactivity. Therefore, in addition to suggesting that SRIF treatment is relatively inefficient in Alzheimer’s disease, the present study also indicates that SRIF is not directly involved in those cognitive functions that were assessed in the present study. These results are in keeping with previous studies (e.g., Cutler, Haxby, Narang, May, Burg, & Reines, 1985; Gray, 1990). The third main finding of this study, was that administration of glucose has no effect upon performance in neuropsychological tasks. Although metabolic abnormalities take place in Alzheimer’s disease (see, e.g., Bowen, 1990), the present results speak against the possibility that these abnormalities have direct effects upon the cognitive deficits seen in this disorder. This said does not, of course, rule out the possibility that metabolic deficits exert long-term effects upon neuronal systems involved in cognitive functioning. 74 CURRENT INVESTIGATION

It should, however, be understood that the present investigation demonstrates that one particular analogue of SRIF, i.e., SMS 201-995, has no beneficial effect on performance in cognitive tasks. From this does not follow, that SRIF treatment is ineffective in Alzheimer’s disease. First, many peptides do not pass the blood-brain barrier directly. Therefore, SRIF treatment would remain unsuccessful: the compound does not reach its target sites in the brain. There are good arguments both for and against this option. Unfortunately, SRIF treatment is a novel approach to treatment of neurodegenerative disorders. Therefore, most results have not yet been published in scientific journals, and remain known to a handful of researchers. For the argument speaks the fact that the dosage of SMS 201-995 can be increased by a factor three hundred without the notice of effects upon the central nervous system (Chase, 1990). In favour of the argument is also the result from a recent, as of yet unpublished experiment, conducted in our own laboratory. In this latter study, 0.075 mg SMS 201-995 was infused in an Alzheimer’s disease patient. Before, during, and after the infusion, fractions of cerebrospinal fluid were continuously drawn. Although SMS 201-995 was readily detectable in the blood, the compound was not found in the cerebrospinal fluid. Against the argument that compounds like SMS 201-995 does not reach the target regions of the brain, stands the possibility that neuropeptides might affect the central nervous system through other routes than the blood-brain barrier. For instance, neuropeptides can alter the permeability of the blood-brain barrier for other substances. Some neuropeptides may have access to the brain through structures that do not possess a blood-brain barrier. Neuropeptides can affect physiological properties of the brain, such as blood-flow. In favour of this possibility speak the results from our own experiment, as referred to above. According to this study, SMS 201-995 affected levels of cerebrospinal fluid SRIF and neuropeptide Y, both not VIR These effects took place, although SMS 201-995 could not be detected in the cerebrospinal fluid. In addition, SMS 201-995 (or the central stimulation of SRIF and neuropeptide Y) caused a rapid increase in intracranial pressure. In conclusion, the question of whether SRIF analogues exert effects upon the central nervous system seem to be void of a conclusive answer. Therefore, the best strategy at the moment might be to await the outcome of ongoing studies. A second reason SMS 201-995 lacks beneficial effects upon cognitive functions, regards differences between methods employed in investigations regarding memory in human and animal subjects. That is, even if investigations regarding cognitive effects of SRIF have failed to document such effects in humans, a different picture is seen in animal research (Bakhit & Swerdlow, 1986; Haroutunian, Mantin, Campbell, Tsuboyama, & Davis, 1987; Vécsei, Bollock, Penke, & Telegdy, 1986; Vécsei, Bollóck, & Telegdy, 1983). Experimental methods directed towards the study of memory in animals often do not address exactly the same components of remembering as human memory tasks. Thus, human memory tasks involve explicit recollection of autobiographical episodes, wherèas animal learning paradigms involve acquisition of procedural skills. Tentatively, therefore, SRIF containing neurons of the association areas of the brain might be important to procedural learning. This suspicion is strengthened by the fact that Alzheimer’s disease patients indeed do show signs of procedural learning deficits. A third circumstance complicating the conclusion of no beneficial effect of SRIF treatment, regards the fact that SRIF levels in the brain and cerebrospinal fluid of Alzheimer’s disease patients vary considerably. Some Alzheimer’s disease patients display levels well within the normal range, others fall dramatically below. It is of course likely that these levels reflect the amount of damage to SRIF-containing neurons in the brain, and that only those patients who evidence some sparing with respect to SRIF will benefit from treatment. This notion is strengthened by findings indicating that damage to somatostatinergic fibers is post-synaptic (e.g., Beal & Martin, 1986). CURRENT INVESTIGATION 75

In sum, the outcome of the current study adds to earlier findings of no cognitive or neuropsychological effects of SRIF analogs in humans. However, given the caveats discussed above, further work is needed. The outcome of the experiment also showed that administration of glucose did not improve cognitive performance. While several investigators have described metabolic abnormalities in DAT patients, the present results speak against the possibility that these abnormalities have direct effects upon the cognitive deficits seen in DAT. This said does not, of course, rule out the possibility that metabolic deficits exert long-term effects upon neuronal systems involved in cognitive functioning. Because of the variation with respect to SRIF in Alzheimer’s disease, the present investigators undertook an effort to relate pre-experimental levels of cerebrospinal fluid SRIF-LI to possible treatment effects, cerebrospinal fluid SRIF-LI was correlated (using Pearson’s r) to the difference between performance in the placebo condition and performance in the three experimental conditions. Using an alpha-level of .05, six out of thirty correlations between cerebrospinal fluid SRIF-LI and the difference scores turned out to be statistically significant5. All these correlations involved administration of glucose; half of which in combination with SMS 201-995. The number of errors in the visuo-spatial task was inversely related to cerebrospinal fluid SRIF- LI in the glucose (r=-0,76) and the SMS + glucose conditions (r=-0,74), suggesting that patients with higher cerebrospinal fluid SRIF-LI levels made relatively fewer errors following administration of glucose. Three measures of short-term remembering were positively correlated to glucose administration calculated this way: primary memory (as determined by the Tulving and Colotla method) following glucose administration (r=0,83); and performance with respect to the recency portion of the serial position curve after administration of glucose (r=0,89) and SMS + glucose (r=0,86). Again, these results suggest that glucose improved the short-term memory capacity of Alzheimer’s disease patients with higher cerebrospinal fluid SRIF-LI. Patients with higher cerebrospinal fluid SRIF-LI did, finally, indicate improvement in the free recall task following administration of SMS + glucose (r=0,89). Although these data support the contention that SRIF and glucose interact in some aspects of cognition, the generality of the present findings is limited by the small number of subjects employed. Future studies should address the association between glucose and cognitive functions specifically. However, it is interesting to note the recent finding of memory enhancing effects of glucose in healthy older and younger subjects (Hall, Gonder-Frederick, Chewning, Silveira, & Gold, 1989). Taken together with the results of the present investigation, a picture emerges where SRIF mediates cognitive and neural effects of glucose. Again, it must be concluded that much work is needed in this area.

EXPERIMENT 4: ENCODING-RETRIEVAL INTERACTIONS IN OLD AGE

Thus far, the studies comprising this dissertation have demonstrated that activities at the time of encoding can influence memory performance in older subjects. This finding applies to 'younger' older subjects, as well as to 'older' older subjects and to subjects suffering from Alzheimer's disease. In particular, active encoding can improve memory performance to a larger extent in older subjects than in younger subjects. Since memory performance in the elderly can be augmented by means of efficient encoding operations, one question is whether this improvement is of equal magnitude in 'younger' and 'older' elderly subjects. Another question is whether processes at retrieval would produce similar

5In order to test the validity of these observations, the CSF SRIF-LI values were correlated to 30 sets of random numbers. In this check, no correlation (in comparison to an estimated 1.5) turned out to be statistically significant. 76 CURRENT INVESTIGATION improvements in younger and older elderly individuals. The aim of Experiment 4 was to contribute to the understanding of these important questions. There are several reasons why processes related to the acquisition and the utilization of to-be-remembered information could be differentially affected at different stages of human aging. First, it could be argued that encoding operations are more dependent upon mental calculation than retrieval operations. That is, by the time of retrieval, part of the information that enters into the convergence between stored information and retrieval information, already exists in the environment Furthermore, some of the processes that constitute remembering have already been executed once (i.e., at the time of acquisition). In contrast, by the time of encoding of to-be-remembered information, the rememberer has to rely upon new calculations to a certain extent. Then, to the degree that retrieval operations are less dependent upon novel processing, and to the degree that retrieval operations can thrive more upon available information (i.e., environmental retrieval cues), it could be expected that retrieval operations should be preserved in ’older' older subjects. In contrast, 'younger' elderly subjects (e.g., subjects in their sixtieth) should be able to utilize the products of more elaborated encoding to boost memory performance. A second reason processes related to the acquisition and the utilization of to-be-remembered information could be differentially affected at different stages of human aging, is more empirical in nature. As already noted elsewhere in this thesis, older subjects often perform similar to younger subjects when memory is assessed by means of recognition tests or cued recall tests (e.g., Ceci & Tabor, 1981; Craik, 1971; Craik & McDowd, 1987; Erber, 1974; Erber, Herman, & Botwinick, 1980; Gordon & Clark, 1974a, 1974b; Harwood & Naylor, 1969; Howell, 1972; Hultsch, 1975; Laurence, 1967; Schonfield & Robertson, 1966; Shaw & Craik, 1989; Smith, 1977,1980; Warrington & Sanders, 1971). However, very little is known about to what extent the relative preservation of effects of retrieval cues can be observed in 'older' older adults as well. Given this state of affairs, it would be extremely important to know to what extent this pattern is preserved in 'older' older subjects. By the same token, a number of experiments have documented deficits in the elderly regarding encoding processes. Are these encoding deficits of equal magnitude across the span of old age? Or, which perhaps is more plausible, are encoding deficits amplified in 'older' aged subjects? To the best of this author's knowledge, these questions have not been addressed in the experimental literature. A third motif behind Experiment 4, was the common observation of preservation of effects of retrieval support in young children. Early in childhood, infants are able to utilize retrieval cues in an effective manner (e.g., Kobasigawa, 1977; Ritter, Kaprove, Fitch, & Flavell, 1973). In contrast, encoding operations develop at a later stage (e.g., Flavell & Wellman, 1977). Although the loss of cognitive skills in old age can not be equated with the growth of cognitive skills in childhood, there exist some similarities that may be theoretically meaningful. Thus, the ability to boost memory performance by means of retrieval cues could be one such similarity. The fourth argument behind Experiment 4, concerned neurobiological differences across the late adult age span. Since such differences often are marked in older subjects, it is important to investigate to what amount these neurobiological differences correspond to cognitive differences. However, although it is conceivable that neurobiological alterations taking place in old age relate to changes with respect to memory function, it is difficult to predict which aspects of remembering that are effected by biological changes in old age. As a first, and necessary, step in such an undertaking, descriptions of changes at the functional level are needed. Given these four considerations, the current investigation compared memory performance in young, 'young-old', and 'old-old' subjects. To investigate age effects upon encoding and retrieval processes, an encoding retrieval experiment was conducted. The subjects studied categorizabie lists of words. Half of the subjects studied words under standard free recall instructions. That is, the CURRENT INVESTIGATION 77 subjects were instructed to memorize as many to-be-remembered words as possible. The other half of the subjects in each age-group were informed about the nature of to-be-remembered materials. That is, the subjects were informed that the to-be-remembered words were selected from a limited number of categories. Furthermore, the subjects were told that this knowledge could facilitate subsequent remembering. In addition to two types of encoding instructions, two different retrieval contexts were employed. At time of testing, subjects were first given free recall instructions. Following free recall, a cued recall test was provided. In this latter task, the subjects were provided semantic retrieval cues (category names). The basic question in Experiment 4 was if a pattern of encoding-retrieval interactions would be different at different stages of the adult age span. More precisely, it was expected that older subjects were more dependent upon the convergence between information provided at time of encoding and retrieval cues available by the time of testing. That is, contextual support would be more critical to younger subjects than to older subjects. Furthermore, it was expected that effects of contextual support provided at time of encoding would appear more age sensitive than contextual support provided at time of testing. More specifically, older subjects in general, and ’old-old' subjects in particular, should be able to utilize retrieval cues provided at time of testing to augment memory performance. However, given the first three points as discussed above, contextual support provided at encoding should be relatively less important to ’old-old' subjects. In the lalter regard, it was more difficult to predict the performance of 'young-old' subjects at the outset. As already noted, almost nothing is known regarding differences s to memory between 'young-old' and 'old-old' subjects. In addition, and what is more important, the ability of a group of older subjects to utilize contextual support is of course also dependent upon factors other than the chronological age of the subjects. For example, the difficulty of the memory task most likely will influence to what extent 'young-old' subjects will look more similar to young adults than to 'old-old' adults.

METHOD

The subjects in Experiment 4 were 60 healthy adults. The younger adults (mean age 21 years) were high school or college students, who participated on a voluntary basis. The group of 'young-old' elderly subjects were 72 or 73 years old, and the 81 or 82 years of age. All elderly subjects were recruited from an ongoing longitudinal investigation regarding health and psychological functions in old age. A series of medical, neurological, and neuropsychological investigations ensured that none of the elderly subjects did suffer from Alzheimer's disease or any other age associated cognitive disorder. The procedure embodied five steps: warm-up, instruction, presentation of to-be-remembered words, free recall, and cued recall. Besides the instructions presented before the presentation of the experimental list, the procedure was identical to all subjects participating in the experiment. Half of the subjects in each age group received standard free recall instructions. These subjects were asked to memorize a list of consecutive words. No mention was made regarding the specific nature of the list of to-be-remembered words. The other half of the subjects in each age group were informed about the semantic nature of the to-be-remembered list. Before the presentation of the experimental list, the subjects were told that the to-be-remembered words were selected from a limited number of semantic categories. In addition, the subjects were also informed that this knowledge could be used to memorize the words in a more efficient manner. 78 CURRENT INVESTIGATION

The to-be-remembered list of words comprised 30 nouns. The order between words was randomized. However, a restriction regarding items from the six semantic categories was imposed. Thus, an item from a specific category could not appear in the list again until items from all the other categories had been presented. Each word was presented visually, using a slide projector. In addition, the subjects were asked to name each word aloud. A new word was presented every sixth second. Following the presentation of the last word, five minutes were allowed for free recall. Subsequent to the free recall trial, an unexpected cued recall test was given. During this test, the names of the six semantic categories comprising the to-be-remembered word list were presented to the subjects as retrieval cues.

RESULTS AND DISCUSSION

The principal finding of Experiment 4 was that of a three-way interaction between group, encoding instructions, and type of testing. The outcome, which can be studied in Table 1 of Experiment 4, essentially suggests two things. First, all groups evidence effects of retrieval cues provided at time of testing. Second, 'younger-old' adults evidenced strong effects of contextual support. These effects were seen following support at encoding, as well as support at retrieval. Third, the outcome suggests multiple causes to the amnesia observed in old age. Although support administered in connection with encoding as well as retrieval improved memory performance in the old, quantitative differences still was observed. The observation suggestive of a three-way interaction between age group, encoding and retrieval, was corroborated by an ANO VA. In this analysis, the three-way interaction between group, encoding, and retrieval was statistically significant (p<05). Post hoc testing, utilizing the Tukey test, confirmed that organizational instructions at encoding, as well as retrieval cues at time of testing, boosted memory performance in ’young-old1 subjects. In the group of 'old-old' subjects, retrieval cues provided at the time of testing improved memory performance. However, the provision of organizational 'hints' at time of acquisition of to-be-remembered information, did not effect memory performance in 82 year olds. In young adults, finally, the provision of retrieval cues at time of testing brought about improvement following organizational 'hints' at time of study. The outcome thus suggests that older subjects vary considerably. In particular, the result is suggestive of qualitative differences between 'younger' and 'older' older subjects. In the present study, and in the current context, 'older' older adults did not utilize organizational hints provided at the time of encoding to the same extent as did 'younger' older subjects. Both groups of older adults were able to utilize retrieval cues to support memory performance. The amount of improvement was larger in older subjects than in the young. A straightforward interpretation of the outcome of Experiment 4, is that encoding operations are altered at a relatively early stage of old age. However, when instructions implementing efficient encoding strategies are provided, 'younger' older adults are able to make up for part of their encoding deficit. As people grow older (in the present context, enter the ninth decade of life), it becomes increasingly more difficult to compensate for declining encoding capabilities. As to retrieval skills, it appears that the ability to utilize semantic retrieval cues to support remembering, is well preserved into the ninth decade of life. In fact, in the context of the present investigation, the benefit of retrieval cues was larger in older subjects than in the young. This data pattern might be taken to mean that age related memory decline is directly related to retrieval difficulties. More specifically, younger subjects might be better at generating aspects of to-be- remembered information that serve subsequent recall when overt retrieval cues are lacking. Since retrieval and search skills in general are preserved in older subjects, remembering occurs when such retrieval aids are provided by the time of testing. CURRENT INVESTIGATION 79

Although the present experiment documents a highly interesting data pattern, less is disclosed concerning possible reasons behind this pattern. As discussed elsewhere in this thesis, many different explanations regarding age associated memory dysfunction has been proposed. The present pattern can be explained by means of several of these theories. One common notion explains age associated memory decline in terms of reduced attentional resources (e.g., Hasher & Zacks, 1979; Craik, 1977a; Craik & Rabinowitz, 1984). Within the present context, it could be argued that encoding operations are more demanding with respect to attentional capacity. Thus, if older subjects are deficient regarding the allocation of attentional resources, then encoding operations would suffer before retrieval processes do so. This interpretation has no explicit backing in the present study. However, other experimenters have shown that retrieval is less affected by competitive attentional demands than encoding processes (e.g., Baddeley, et al., 1984). Alternatively, the pattern observed in the present experiment could be due to specific lesions to retrieval mechanisms (taking place relatively early during the course of aging), and (during a later stage of aging) damage to encoding or storage mechanisms. This explanation is just as valid as the foregoing explanation. However, the problem is that no one knows what the putative mechanisms involved looks like or functions as. At present, it is difficult to see how these brain mechanisms can be studied empirically. As long as this situation lasts, explanations of age-associated memory decline in terms of damage to specific retrieval or encoding mechanisms, remain loose ends. A second problem with the latter type of explanations, regards the fact that it does not follow that qualitative differences between 'young-olds' and 'old-olds' should take place. Explanations of age-related memory decline in terms of attentional or 'capacity' deficits can make room for such findings. That is, it can be postulated that capacity limitations are augmented with increasing chronological age. Such limitations could then interact with task demands to give rise to a pattern similar to the one observed here. Therefore, it is reasonable to proceed through the study of effects of capacity limitations upon encoding and retrieval of to-be-remembered information.

EXPERIMENT 5: EFFECTS OF PRIMING AND CUED RECALL IN ELDERLY, SLEEP DEPRIVED AND ALCOHOL INTOXICATED SUBJECTS

The previous experiment provided two findings. First, 'young-old' subjects were more apt at utilizing organizational instructions provided at the time of encoding of to-be-remembered information, than were 'old-old' subjects. Second, the ability to utilize retrieval cues was spared in all age-groups studied. This pattern replicates and extends the outcome of many previous findings. Unfortunately, it is not clear how the findings of Experiment 4, as well as related investigations, should be interpreted in detail. The finding of preserved effects of semantic retrieval cues in the elderly could be taken to mean that retrieval operations are spared in the elderly. However, the finding can also be interpreted in opposite terms: older subjects benefit more from retrieval cues, since these subjects actually are incapacitated by a retrieval deficit. Finally, as already mentioned, the pattern could be understood in terms of the distinction between automatic and effortfull processes (e. g., Hasher & Zacks, 1979). To a varying degree, retrieval involves the reconstruction of an event that already has taken place at least once. It is possible to assume that under most circumstances, the 're-processing' of an event demands less attentional capacity than the initial processing of the very same event. Therefore, the finding of preserved retrieval skills in old age could be the inverse relation between retrieval operations and attentional demands. The outcome of a series of experiments carried out by A. Baddeley and associates speaks in favour of this third interpretation. In an ingenious investigation, Baddeley, Lewis, Eldridge, and Thompson (1984) demonstrated that concurrent activity disrupted acquisition of to-be-remembered 80 CURRENT INVESTIGATION

information. However, concurrent activity did not impair retrieval of already acquired information. This latter finding was obtained in episodic, as well as semantic memory tasks. The aim of the two concluding experiments in this series, was to further the knowledge regarding encoding-retrieval interactions in old age. In particular, it was regarded important to know to what extent the interaction between encoding-retrieval interactions and age can be understood in terms of cognitive capacity. There are very few investigations which have addressed the questions discussed here. However, recently two reports have been published which, when combined, would allow for the study of the issues discussed in the present context. First, Rabinowitz (1986) investigated the impact of chronological age upon three aspects of remembering: performance in a cued recall task, a recognition memory task, and priming. The three tasks were assumed to reflect varying demands for cognitive capacity: the cued recall tasks being the most demanding task, and the priming task being the least demanding task. As predicted from a 'capacity hypothesis' (e. g., Hasher & Zacks, 1979), age effects were abundant in cued recall, small in the recognition task, and absent in the priming task. Rabinowitz interpreted these findings as reflecting retrieval deficits in old age. Since older adults evidenced priming effects of equal magnitude as young adults, encoding processes must have been intact. However, when retrieval demands are increased, typical age differences are observed. Although the interpretation of spared priming effects appears to be highly problematic, the experiments reported by Rabinowitz suggest how the question can be addressed. A second investigation of relevance to the present undertaking, regards a study by McKoon and Ratcliff (1979). This investigation adds two additional features to the experiment discussed by Rabinowitz. First, McKoon and Ratcliff utilized a paired-associate learning procedure. This task embraced strongly associated word pairs, as well as weakly associated pairs. Second, McKoon and Ratcliff utilized a semantic memory task, in addition to an episodic cued recall task. The basic idea behind Experiment 5 was to combine the methods of these two investigations, in order to study the effects of cognitive capacity upon encoding and retrieval in old age. If older subjects suffer from an encoding deficit, then it follows that items studied under difficult conditions ought to be difficult to remember. On the other hand, if old adults suffer from a retrieval disorder, then it should be difficult to gain access to information under conditions of effortfull retrieval. Finally, if older adults are impaired when remembering takes place under effortfull conditions - regardless of the encoding-retrieval distinction - then older adults should be disadvantaged when encoding, as well as retrieval, demands cognitive effort. However, when encoding or retrieval does not demand cognitive effort, effects of aging should be mitigated. More specifically, the experiment reported in the present study embraced three different phases. During the first phase, subjects studied word pairs (i.e., paired associates). Some of these word pairs embodied*strongly associated words (e.g., 'doctor - nurse'). Other word pairs embodied weakly associated words (e.g., 'needle - nurse'). The second phase of the experiment was a lexical decision task. In this task, the subjects were presented letter strings on a computer screen. For each string, the subject was asked to decide if the string was a real word or not. In the present investigation, this lexical decision task was employed to bring about several different types of priming. Semantic priming was brought about through the presentation of a semantically related word before the presentation of a target word. Episodic priming could be assessed when two weakly associated words were present in the lexical decision task, as well as during the initial presentation of to-be-remembered word pairs. The third phase of the experiment was a cued recall test. In this task, the subjects were presented with the first word of each pair and were then asked to remember the accompanying word. CURRENT INVESTIGATION 81

The combination of tasks employed here, permitted the assessment of effects of cognitive effort upon encoding and retrieval of to-be-remembered information. As to encoding processes, it was assumed that encoding of word pairs with a high level of pre-experimental association constitute an example of relatively automatic encoding. This assumption is based upon the fact that these associations already exist in semantic memory; before study. Furthermore, it was assumed that encoding of words with a relatively low degree of pre-experimental association exemplifies effortfull encoding. As to retrieval, it was assumed that priming reflects automatic retrieval of information. In contrast, then, cued recall represents more effortfull retrieval. The important thing about the present study regards the fact that it manipulates degree of cognitive effort at encoding as well as retrieval. Thus, if the degree of effortfull processing affects the magnitude of the age effect, older and younger adults should perform similarly when performance is assessed by means of priming, and when encoding involves learning of word pairs with a high degree of pre-experimental association. Similarly, age effects ought to be marked when encoding involves learning of word pairs with a low level of pre-experimental association; and when retrieval is assessed by means of cued recall. On the other hand, if older adults perform poorly on the cued recall task (irrespective of the degree of semantic relatedness between items), then damage to circumscribed retrieval mechanisms would be implicated. Finally, if encoding processes were at stake, then memory impaired subjects should evidence equal difficulties for items with a high degree of semantic relatedness, as well as items with a low degree of semantic relatedness. Besides the investigation of older subjects, the present experiment also involved two groups of subjects having experimentally induced amnesia. One of these groups was alcohol intoxicated, and the other group sleep deprived during testing. The reasons for including these two groups were as follows. First, it has been suggested that alcohol intoxicated subjects evidence a memory disorder that resembles age associated memory dysfunction (Craik, 1977b). In particular, recent evidence suggest that older subjects (e.g., Craik & Rabinowitz, 1984), as well as alcohol intoxicated subjects (Hashtroudi, Parker, DeLisi, Wyatt, & Mutter, 1984) evidence deficits regarding elaborative processing. Both groups of subjects tend to process information in a somewhat rigid and stereotyped manner. Although the mechanism behind this deficit has not been elucidated, it is often assumed that the dysfunction is due to depleted processing resources. As to sleep deprived subjects, little is known about the amnesia taking place subsequent to sleep loss. It is only recently that researchers have begun to investigate memory dysfunction following sleep loss (see, e. g., Elkin & Murray, 1974; Polzella, 1975). However, it is likely that sleep loss leads to a depletion of cognitive resources. Consequently, sleep deprived subjects can be expected to perform in a manner similar to older subjects and alcohol intoxicated subjects. A second reason behind the inclusion of alcohol intoxicated subjects and sleep deprived subjects in the current experiment, regards the more general question of similarities and differences between memory disorders of varying etiology. It can safely be stated that findings implicating common mechanisms behind memory disorders of varying etiology would be of substantial importance. On the other hand, the description of qualitative differences between different memory disorders would also be significant, not the least in a clinical context. Such findings could presumably aid in the clinical diagnosis of amnesia. To summarize, Experiment 5 embraced four groups of subjects: young controls, older, healthy subjects, alcohol intoxicated subjects, and sleep deprived subjects. Each subject participated in two tasks: a cued recall task and a lexical decision task. Furthermore, before the administration of these tests, the subjects studied word pairs. Half of those embodied strongly associated words; the other half weakly associated words. If memory disorders in the elderly, alcohol intoxication and following sleep loss are due to deficiencies as to effortfull processing, then impairment should be 82 CURRENT INVESTIGATION observed as to cued recall of weakly associated word pairs. Conversely, memory dysfunction should be eliminated as to priming of strongly associated word pairs. The remaining combinations of experimental conditions should fall between these extremes.

METHOD

The subjects were all healthy volunteers. The three groups of younger subjects were all between 20-30 years of age. The mean age of the older subjects was 70 years. The subjects in the alcohol intoxication group were given an equivalent of .90 ml/kg of body weight ethanol. The alcohol was consumed in the form of vodka mixed with orange juice. The subjects were allowed fifteen minutes for the consumption of the alcohol. Twenty minutes later, blood alcohol levels were analyzed, by means of a Lion ’breathalyzer1 (Lion S-D2 Alcometer). BAL were then sampled until a particular subject had exceeded a BAL of .032 g/100 ml. (This level corresponds to .4 per mille alcohol). The mean BAL values were .054 g/100 ml and .058 g/100 ml for male and female subjects, respectively. Subjects were kept under observation in the laboratory for four hours after the experiment. All testing was carried out in the morning; each session started 8:00 a.m. Regarding the group of sleep deprived subjects, the procedure was as follows. All subjects arrived at the laboratory at 4:00 p.m. The subjects then remained at the laboratory until testing took place, the next morning. The subjects were not allowed to sleep during the night. In addition, the subjects were not allowed to consume coffee, tea, or other psychostimulants during the morning. The subjects were instructed to wake up at 8:00 a.m. on the morning before the experiment. Testing did not take place until a particular subject had been awake for 24 h. The mean time of sleep loss was 26 h. Each subject was tested individually. The experiment comprised three main phases: (a) presentation of word pairs for study; (b) lexical decision task; and (c) cued recall of word pairs. Subjects were presented 12 experimental lists, and two practice lists. Each list comprised six A - B word pairs. The word pairs were presented on a computer screen for 4 sec/pair. Subsequent to the presentation of the concluding item, a row of asterisks signalled the beginning of the lexical decision task. This task comprised 14 words and 9 non-words. These items were presented one by one, and remained in sight until the subject pressed a predefined key, thus indicating whether an item was a real word or a nonsense word. An interval of 200 msec elapsed between each item. Five seconds after the presentation of the last item in the lexical decision list, the cued recall test or a novel list was presented. Cued recall tests were given following the practice lists, lists number six and twelve. In the cued recall test, the A members of the word pairs were presented on a paper. The subjects were asked to write down the accompanying B words. Regarding the lexical decision task, five types of relations between primes and targets were present: (a) episodic priming of weakly associated words; (b) episodic priming of strongly associated words; (c) semantic priming of strongly associated words; (d) priming of unrelated words for base rate control; (e) priming of non-words. For the first two of these experimental conditions, the prime and the target were presented as a word pair in the study list. For the ensuing two conditions, the target was always present in the study list. However, in these latter cases, the prime did not appear in the study list. Each of the twelve experimental lists contained one item from each priming condition involving words. As to non-words, these were never present in the study list. The amount of priming was determined by the difference in reaction time between the control condition and the three experimental conditions for words. Thus, the experiment assessed episodic priming of weakly related words, episodic priming of strongly related words, and semantic priming CURRENT INVESTIGATION 83 of strongly related words. Two measures of priming were calculated: one absolute measure, and one relative measure. These measures were calculated through subtraction of target items belonging to the first three priming conditions from target items belonging to the condition involving priming of unrelated words. Since there were twelve experimental lists, a mean value was calculated for each subject and priming condition. The material was constructed according to the guidelines as described by McKoon & Ratcliff (1979). The Swedish words were selected from Shaps, Johansson, and Nilsson (1979). Words with a strong degree of semantic relatedness had a mean association value of 22%; words weakly associated had an association value of 2%.

R e s u l t s

Priming. The results with respect to the lexical decision task indicated over-all differences in reaction time between young controls and sleep deprived subjects on the one hand, and alcohol intoxicated and elderly subjects on the other hand (p<001). In particular, older subjects were slower than the other groups. More interestingly, the differences as regard priming effects were small. All four experimental groups evidenced statistically significant effects of priming (p<.05). However, no statistical evidence for an interaction between group and type of priming was obtained. This outcome remained, despite the employment of several different methods for scoring and analyzing the data. As to the difference between different types of priming, a statistically reliable main effect of priming condition was obtained. The reason behind this effect was that the condition involving episodic priming of strongly associated words yielded larger priming effects. Cued recall. In contrast to the priming task, the three groups of memory impaired subjects evidenced deficits as to cued recall of weakly associated words. This deficit was not observed with respect to cued recall of strongly associated words (Group X Strength of association interaction p<.005).

DISCUSSION

The outcome of the present experiment indicates deficits as to effortful memory processes in the aged, in alcohol intoxicated subjects, and in sleep deprived subjects. This finding is of obvious importance, since chronological age, drug intoxication (and alcohol intoxication in particular), and tiredness represent common causes to memory dysfunction in everyday life. The outcome of the present experiment suggests that automatic encoding processes are spared in the three groups of memory impaired subjects employed here. The reason behind this conclusion is the fact that all groups of subjects evidenced superiority as to priming and cued recall of strongly associated words. If automatic encoding processes were impaired, then an attenuated superiority for strongly related words would have been expected. The outcome of the current experiment also evidenced a sparing of automatic retrieval processes. This can be deduced from the fact that memory impaired subjects evidenced priming effects of a magnitude equal to controls. In contrast (and as already mentioned), memory deficits were obvious as to cued recall of weakly associated words. The interpretation suggested here - i.e., effortful memory processes are at stake in memory impairment - rests upon two assumptions. The first assumption is that priming taps automatic retrieval to a larger degree than cued recall. Nowadays, this assumption is probably not contentious. Many theorists have inferred that priming in the lexical decision task is based upon a spreading of activation between related concepts, pathways, or nodes (e.g., Anderson, 1983; Collins & Loftus, 84 CURRENT INVESTIGATION

1975). Other writers have emphasized the cue-dependent nature of priming (Ratcliff & McKoon, 1988). However, regardless of the details of the mechanisms underlying priming, most theorists agree that the retrieval subserving priming is automatic. The idea that priming under most circumstances represents automatic retrieval is supported by the finding of preserved priming in aging and organic amnesia (e.g., Moscovitch, 1982b). A second assumption regards encoding. It is proposed that encoding of highly associated words also is an example of a process that often is automatic. The encoding of strongly associated words requires an activation of units already available in memory. However, weakly associated words require additional processing. The inability to carry out such processing could contribute to the amnesia observed in the present study. In the context of the present thesis, the outcome adds to the understanding of how memory dysfunction interacts with encoding and retrieval processes. In particular, it was observed that effortful retrieval processes can add to the memory impairment seen in aging, alcohol intoxication, and sleep deprivation. This finding suggests that the sparing of cued recall performance observed in Experiment 4 is due to task demands, rather than a selective sparing of retrieval mechanisms in old age.

EXPERIMENT 6: WORKING MEMORY IN OLD AGE

As discussed previously in this dissertation, it is a common theme in explanations of age- associated memory impairment that memory difficulties in the elderly might be causally related to depleted attentional resources. Thus, investigators describing encoding deficits in the aged have often attributed these deficits to difficulties in allocating attentional resources (Craik, 1977a; 1983; Craik & Byrd, 1982; Simon, 1979). Similarly, authors studying retrieval deficits in elderly persons have explained such problems in terms of difficulties in carrying out effortfull search operations (Burke & Light, 1981; Nilsson, Bäckman & Karlsson, 1989). In the present context, it has been shown that (a) memory impaired subjects can utilize activities at encoding and retrieval cues at time of testing; (b) effortful memory processes are impaired in aging, as well as other forms of mild amnesia; (c) elderly subjects, varying in mean age with as little as 9 years, nevertheless evidence qualitative differences as to remembering. Therefore, an explicit test of the contribution of attentional deficits to memory impairment in the aged is called upon. In general, important aspects of older persons' memory problems could be understood in terms of limited attentional resources. However, explicit tests of the contribution of attentional deficits to memory impairment in the aged are relatively rare. The contemporary literature comprises four studies addressing this topic, specifically. These are studies by Wright (1981); Baddeley, Logie, Bressi, Della Sàia, and Spinnler (1986); Stark, Craik and Morris (1988); and Morris, Stark, and Craik (1988). Wright (1981) administered a digit recall task, either alone or in combination with a secondary task. The results showed that older subjects performed inferior to younger adults. However, older persons were not per se more penalized than their younger peers when the arithmetic task was added to the situation. Stark, Craik and Morris (1988) and Morris, Stark and Craik (1988) recently reported studies designed to study different aspects of working memory (Baddeley, 1986) in the aged. These investigators found that older persons were outperformed by younger adults in most tasks used. However, the magnitude of age differences was unaffected by the difficulty of the task, i.e., working memory involvement. Finally, Baddeley, Logie, Bressi, Della Sala, and Spinnler (1986) studied working memory in a group of patients with Alzheimer's disease, healthy older persons, and younger persons. These authors used an auditory short-term memory task as the primary task and manual tracking as the secondary task. The addition of a secondary task did not CURRENT INVESTIGATION 85 cause a larger drop in performance in healthy older adults than in younger adults. However, patients with Alzheimer's disease were more penalized than healthy younger and older adults by the addition of a secondary task. These studies, using primary and secondary tasks, resemble each other in three different ways. First, deficits with respect to attention and working memory do not seem to be of particular importance to memory problems occurring in late adulthood. This is surprising, since many authors have stressed attentional mechanisms in this regard (Craik, 1977a; 1983; Craik & Byrd, 1982; Hasher & Zacks, 1979; Welford, 1958). Second, most of the investigations dealing with the contribution of attentional deficits to memory problems in elderly subjects have utilized short-term memory tasks, tapping temporary storage of information. In the aged, it is possible that attentional mechanisms are crucial to long­ term aspects of remembering, rather than short-term aspects of remembering. This is so, especially since aging effects often are diminished in tasks addressing temporary storage of information (e.g., Craik, 1977a). Third, the experimental tasks employed in studying effects of attentional factors upon remembering primarily tap upon encoding of to-be-remembered material. That is, the capacity- demanding secondary task has been administered in conjunction with registration or learning of the critical information. In the aged, however, faulty attentional mechanisms might be more detrimental to access or retrieval of already established memories. If investigators so far have been unable to verify that the older persons' attentional problems contribute to their memory impairment, it could be since the influence of attentional mechanisms upon retrieval operations — or the combination of encoding and retrieval operations — has not been investigated. Given these concerns, the purpose of the present investigation was to study the effects on the encoding and retrieval of a primary task as a function of performing a secondary task. This was accomplished by presenting subjects lists of words for subsequent recall as the primary task and with card sorting as the secondary task. For one fourth of the lists, subjects were engaged in the card sorting task during presentation of the word lists. For another fourth of the lists, subjects were engaged in the card sorting task during recall of the word lists. For still another fourth of the lists, subjects carried out the card sorting task during both presentation and recall of the words of a list. Finally, for the remaining fourth of the lists, there was no secondary task given, neither at study nor at test. This dual task paradigm was originally described by Murdock (1965). Recently, Baddeley, Lewis, Eldridge and Thompson (1984) used this method to study the importance of working memory for encoding and retrieval of information in young adults. Baddeley et al. (1984) found that engaging working memory in a secondary, card-sorting task, impaired performance if this secondary task was administered in conjunction with encoding, but not retrieval. Similarly, performance in a semantic memory task (i.e., retrieval from semantic memory) was unaffected by the secondary task.6 The outcome of the studies by Murdock (1965) and Baddeley et al. (1984) demonstrates unambiguously that attentional factors affect remembering. In addition, the outcome of the study by Baddeley et al. indicates that attention plays a more important role to encoding than it does to retrieval. Most important for the present objectives, the studies by Murdock (1965) and (in particular) Baddeley et al., suggest a direct method of studying the contribution of attentional factors to encoding and retrieval of information, not only in young persons, but in the aged as well. It was assumed, that older individuals would be more penalized by carrying out a secondary task during encoding, if encoding deficits are predominant to memory problems in the aged. Similarly, if retrieval deficits are especially important in accounting for the older subjects' memory

6For related discussions on attention, short-term memory, and problem solving, see Hitsch, 1980; and Bourne, Ekstrand and Dominowsky, 1971. 86 CURRENT INVESTIGATION disturbances, then the administration of a secondary task in conjunction with retrieval should affect performance. The present study included three groups of subjects: one group of young, healthy adults, and two groups of elderly, healthy adults. It was regarded as particularly important to ensure that only healthy, non-demented persons were assessed since Baddeley et al. (1986) found that patients suffering from Alzheimer's disease - not healthy older persons ~ displayed deficits with respect to working memory. A unique feature of this experiment is the fact that it was possible to determine that none of the subjects participating in the present experiment showed signs of accelerated loss of memory or other cognitive functions during a six-year interval, as determined by the data from an extensive, six-year longitudinal study, in which the two groups of elderly subjects participated.

METHOD

Three groups of subjects participated in the experiment: one group of younger, healthy adults, and two groups of older, healthy adults. The mean ages of the three groups were 24 years, 76 years and 85 years, respectively. Each group comprised six females and six male subjects. The younger subjects were university students. The two groups of elderly subjects were examined in conjunction with a longitudinal study on health and cognitive functioning, which had been going on for six years. These persons had been tested at two occasions (three and six years) before the present investigation. The younger of the two groups of elderly persons consisted of individuals bom in 1911. The older group of elderly consisted of persons bom in 1902. All individuals were administered a battery of neuropsychological tasks. The subjects were seated in a quiet room and were instructed that they were to remember lists of words, which the experimenter would read to them at a rate of one word every two sec. When the presentation of each list was completed, the task was to recall as many words of that list as possible, in any order they preferred. Ninety seconds were allowed for this free recall test. Subjects were also informed that for some of the lists they would be asked to perform an additional task. This additional task, they were told, was to occur when the word-lists were read, in some cases and during testing in other cases. The nature of the secondary task was explained in due course, as the session proceeded. This basic procedure was repeated for an unspecified number of times. The secondary task was a card-sorting task. Subjects were handed a deck of playing cards, and were asked to sort the cards into two piles, according to colors (black or red). For two of the lists, subjects were asked to sort the playing cards while the words were read out by the experimenter; i.e., during encoding. For two other lists - during retrieval - subjects were asked to sort the cards during testing. For still two other lists, the subjects sorted cards, during both presentation and testing. Finally, the presentation and test of two more lists comprised no card-sorting. In order for the experimenter and the subjects to maintain adequate pace, an audio cassette was prepared. This cassette contained 51 discrete but easily recognizable signals, sounding at every two seconds. Before the signaling started, a "get ready" message was presented. The subjects were asked to turn a new card every time the signal was heard, and to place the card on the appropriate pile before the next signal would occur. The cassette tape was used for all conditions, irrespective of whether a particular list involved card-sorting or not. Two different presentation orders were used. In addition, the ordering between tasks was balanced within each group of subjects. The words comprising the to-be-remembered material were randomly allocated to eight different lists. CURRENT INVESTIGATION 87

RESULTS AND DISCUSSION

Three features of the data should be noted. First, there are marked differences in performance between, on the one hand, young adults, and the elderly subjects on the other. Second, distraction during encoding, and during both encoding and retrieval produce clear suppression of performance. Distraction during retrieval only yields a somewhat smaller decrement. Third, there is no apparent sign of an interaction between age and type of distraction, which would have occurred if older individuals were relatively more penalized by an increase of the attentional load. These observations were supported by a series of ANOVAs. For the purpose of the present investigation, the most interesting analyses were those regarding the possible interactions between the age factor and the two factors involving distraction. No such interaction effect approached statistical significance. The present experiment was undertaken to study the contribution of attention to the memory impairment occurring in normal aging. In contrast to the widely held belief that depletion of attentional resources is an important determinant of memory impairment in the aged, the results of this experiment failed to evidence that attentional load impaired memory performance to a larger extent in the aged than in younger adults. The outcome of the present study suggests that attentional load does not impair performance to a larger extent in older adults than in younger adults, when (a) the memory task involves remembering of amounts of information surpassing the size of the memory span for words or digits, i.e., somewhat larger amounts of information and (b) taps permanently stored information. Basically, this outcome is similar to several previous studies, focusing upon temporary storage of smaller sets of information (Baddeley, et al., 1986; Gick, Craik & Morris, 1988; Morris, Gick & Craik, 1988; Wright, 1981). The present investigation also failed to evidence that encoding or retrieval processes in the elderly are particularly vulnerable to an increase in attentional load. This finding could be understood in two ways. It could well be that encoding operations or retrieval operationsare defective in the aged, but that this impairment has nothing to do with attention. Or, it could be that the memory problems seen in aging are more closely related to covert events occurring between encoding and retrieval. The former interpretation might well be correct; however, at the present stage, it seems to be impossible to describe the exact nature of what it would be that disrupts encoding or retrieval. The latter explanation is interesting, because it parallels conceptualizations of human amnesia. Amnesia in humans might occur, because of an inability to further processing of information, once it has been registered and analyzed (McClelland & Rumelhart, 1986; Squire, Cohen & Nadel, 1984). The fact that an increase of the attentional load is not more disruptive to older than to younger adults might come about, since consolidation of memories presumably occurs over longer time periods, and, consequently, is less sensitive to temporary fluctuations of attention. Given that allocation of attentional resources apparently is weakly related to short-term (Baddeley, et al., 1986; Gick, Craik & Morris, 1988; Morris, Gick & Craik, 1988; Wright, 1981) and, possibly, long-term aspects of remembering (present study), how are these findings to be reconciled with findings of reduced attentional capacities in the aged? Tentatively, it might be suggested that the elderly thrive more upon allocation of attentional resources in many cognitive tasks (e.g., reading, problem solving). Among other things, this comes about as an effect of reduced memory skills. Despite the outcome of the present study, we would argue that the correlation between memory problems and attentional deficits is real. However, it might be that the causal ordering should be adjusted: difficulties at allocating attentional resources might occur in the context of memory problems, not the other way around. 88 CURRENT INVESTIGATION

DISCUSSION AND CONCLUSIONS

The objective of this dissertation was to study aspects of memory impairment. More specifically, the purpose was to clarify if, and to what extent memory impaired subjects could employ encoding and retrieval procedures to improve memory performance. To this aim, healthy older subjects, Alzheimer’s disease subjects, sleep deprived subjects, and alcohol intoxicated subjects were examined. In particular, elderly subjects of varying age were studied. This concluding discussion (a) briefly summarizes the empirical outcome; (b) proposes practical implications of the current findings; and (c) proposes theoretical implications of the results.

EMPIRICAL FINDINGS

In general, the experiments reported have demonstrated that all groups of memory impaired subjects were able to improve memory performance. Of particular importance is the fact that this applied to patients suffering from Alzheimer’s disease as well. Thus, there are at least some encoding and retrieval manipulations that can be utilized to foster remembering, even in severely impaired subjects. Of profound importance is also the finding of similarities between different groups of memory impaired subjects. In particular, Experiment 5 is the first study ever to report preserved priming effects in sleep deprived subjects. As to comparisons between ‘young-old’*and ‘old-old’ subjects, certain differences were noted, though. In Experiment I (employing a generation paradigm) ‘old-old’ subjects evidenced larger improvement following self-generation of to-be-remembered information. In Experiment 4 this picture was reversed - ‘young-old’ older subjects evidenced relatively larger performance increments than ‘old-old’ subjects. Finally, in two of the experiments (Experiment 2 and 6), similar patterns were noted for ‘young-old’ and ‘old-old’ elderly subjects. In general, the pattern of data with respect to older, healthy subjects, suggests a relatively complex pattern influencing when older subjects (and perhaps memory impaired subjects in general) will improve from a specific encoding or retrieval manipulation.

PRACTICAL IMPLICATIONS

As to practical implications of the current findings, it is important to note that certain encoding and retrieval manipulations can bring about memory improvement even in severely impaired subjects. Thus, the motor coding task (SPT paradigm) used in two of the current studies yielded memory improvement in Alzheimer’s disease subjects. It can be concluded, therefore, that even Alzheimer’s disease patients evidence a certain spare capacity with respect to memory performance. Whether motor coding can be used in practical settings to boost memory performance in Alzheimer’s disease and other forms of amnesia was not addressed here. One likely problem associated with motor coding as a mnemonic device, is related to the restriction of learning materials employed. In the present dissertation, subjects memorized short acts. If amnesic patients ever will be able to use a particular mnemonic device in a meaningful manner, it is likely that this device must embrace longer sequences of meaningful activities. Given the current demonstration of preserved effects of motor coding in Alzheimer’s disease, the generalization of this effect into more complex situations now becomes a task of utmost importance. It is possible that the preservation of the motor coding effect is one example of the hyperspecificity of memory and learning commonly seen in amnesia. Although amnesic patients at CURRENT INVESTIGATION 89 times can acquire new skills, the utilization of such skills is highly dependent upon the reinstatement of the original learning concept. The motor coding task employed in the current studies does not generalize beyond this point. However, given the current demonstration of preserved effects of motor coding in Alzheimer’s disease, the generalization of the motor coding effect into more complex situations now becomes a task of utmost importance.

THEORETICAL IMPLICATIONS

The theoretical implications of this dissertation can be divided into two questions: implications with respect to theories of memory dysfunction, and implications as to theories of memory.

Implications for theories of memory impairment

One of the basic aims of this study was to utilize experimental methods and cognitive concepts in order to answer three questions: (a) do different forms of memory function differ mainly in terms of severity, or are there distinct types of memory impairment; (b) are there qualitative differences between ‘young-old’ and ‘old-old’ subjects; and (c) is memory impairment caused by deficits as to effortful processes? As to the first question, the current studies did not disclose any qualitative differences between older subjects, alcohol intoxicated subjects, and sleep deprived subjects (Experiment 5) and between healthy and demented older subjects (Experiment 2). Rather, differences between different types of memory impairment were quantitative in nature. The present finding offunctional similarities between different types of memory dysfunction is an important parallel to the recent findings of biological similarities between different forms of memory dysfunction. In particular, intact memory performance seem to be dependent upon the integrity of the hippocampus and the cholinergic system of the brain. Consequently, treatment of memory dysfunction of varying etiologies may be targeted against the same structures of the brain. With respect to similarities and differences between ‘young-old’ and ‘old-old’ subjects, the present study indicates a relatively complex pattern. Depending upon factors which at this moment is poorly understood, ‘old-old’ subjects can at times evidence larger performance gains than ‘young-old’ subjects. At other occasions, the pattern is reversed. In the current context, ‘old-old’ elderly subjects evidenced marked memory improvement following self-generation of words. However, when self-generation embraced motoric actions, performance gains were similar in ‘young-old’ and ‘old-old’ subjects. When encoding comprised a more subtle instruction, semantic organization, ‘young-old’ subjects evidenced larger gains in performance than ‘old-old’ subjects, as well as young adults (Experiment 4). The pattern obtained lends itself to several comments. The pattem obtained regarding comparisons between ‘young-old’ and ‘old-old’ adults, can be understood as follows. First, whenever retrieval support was provided, older adults consistently improved performance (Experiments 2,4, and 5). This data pattem suggests that retrieval mechanisms are impaired in the elderly. If this was not the case, why should older subjects at times benefit more from the provision of additional retrieval information than young adults? Second, the obvious fact that elderly subjects consistently were able to use retrieval cues, suggests that at least certain retrieval processes are spared in the elderly. If this was not the case, elderly subjects should be unable to utilize retrieval cues. Interestingly enough, the results from Experiment 5 suggest when retrieval capacity is spared in the elderly, namely when retrieval is automatic. In Experiment 5, priming was hypothesized to 90 CURRENT INVESTIGATION

reflect automatic retrieval processes. Elderly subjects, as well as alcohol intoxicated and sleep deprived subjects, all evidenced spared priming effects. Regarding aging, this finding is in keeping with previous results. As to alcohol intoxication and sleep deprivation, the finding is novel. Thus, it is possible that at least one, relatively automatic, component of retrieval mechanisms is spared in the aged. It is also possible that the relative sparing of performance in implicit memory tasks and recognition tasks, reflects the workings of a spared retrieval mechanism. Future work should clarify this issue. With respect to encoding operations, the results from this study suggest that properties of the encoding activities are crucial to the effectiveness of remembering in old-old subjects. Thus, when the task fosters activity on behalf of the rememberer, memory deficits are attenuated (Experiment 1 and 2). However, when the task contains less obvious prompts to analysis of the to-be-remembered material, young-old subjects benefit more than old-old subjects. As to mechanisms associated with memory dysfunction, and age-related memory dysfunction in particular, it has already been mentioned that the outcome of Experiment 5 suggests a relative sparing of automatic aspects of retrieval. The outcome of Experiment 6 lends indirect support to this notion, in that engagement of working memory does not impair older subjects to a larger degree than younger adults.

Implications for cognitive theories of memory

One of the most important reasons to study memory impaired subjects, is because such investigations have given insights with respect to the workings of normal memory. What do the current results tell in this regard? The pattern of results in the current thesis shows that memory impaired subjects were just as sensitive to contextual manipulations that yield increase in memory performance, as were healthy, younger controls. This pattern lends support to the view put forward in the introductory section of this chapter, namely, that memory performance can be supported by means of multiple types of input. Even if the biological capacity of the brain is permanently damaged (such as in Alzheimer’s disease) or temporarily altered (such as in alcohol intoxication or following sleep loss), the memory impaired subject is still able to boost memory performance. A common notion as to the representation of memories, is that memories are stored in the form of traces or engrams. In addition, these engrams are supposed to contain multiple attributes of stored information (Bower, 1967; Estes, 1991; Tulving, 1983; Underwood, 1966). The result of the present investigation is clearly compatible with these assertions. At least some attributes of the memory trace can be the product of activity on behalf of the rememberer. That is, if the rememberer is engaged in activity during encoding, it is likely that this activity also adds attributes to the memory trace. Evidently, the ability to add additional features to memory traces is not eliminated in some forms of memory disorder. If the memory trace consists of multiple attributes, some of which can be permanently recorded even by severely impaired subjects (e.g., Experiment 2), one might wonder if there are differences between healthy and impaired subjects as to the experience of remembering. That is, beyond mere differences as to memory performance (healthy subjects remember more information than impaired subjects), do the experience of remembering ‘feel’ different to the memory impaired individual than it does to the normal individual? If the hypothesis put forward here is correct, then memory impaired subjects are able to add some features to their engrams, and not other features. Are these features (which, for instance, are the product of activity and elaboration during encoding) sufficient to yield a recollective experience? Or, can memory impaired subjects ‘remember’ only when memory performance is assessed indirectly, or by means of strong retrieval cues (e.g., copy cues in a recognition test)? CURRENT INVESTIGATION 91

Obviously, this question is not addressed in the current dissertation. However, the point to note is that the present findings raise additional questions, questions whose answers could be of profound importance to further the understanding of memory dysfunction, and memory in general. 92 REFERENCES

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