Drugs and Human Memory (Part 1)

Received from the Department of Anesthesia, The University of Iowa, Iowa City, Iowa.TABLEEVERYTHING in life is memory, except for the thin evanescent slice of the present. Memory is a crucial and sustaining mental function that shapes our existence. All other cognitive functions would be meaningless or impossible without the ability to record and recall previous experience. Memory, in addition to bringing learned facts and ideas back to mind, affects our behavior in an unconscious way. We lose the connection to ourselves and with others, and life becomes void of its essence as tragically displayed in patients with severe dementias when memory is lost. Memory research is one of the most fascinating and flourishing areas of science today. A revolution has occurred in our knowledge and understanding of the capabilities and failures of this fascinating mental function, and what happens to the brain when we learn, remember, and forget. There have also been some recent advances in the search for memory-enhancing drugs. Development and testing of drugs for prevention and treatment of patients with impaired memory are vital in a world with a progressively increasing age population.Memory as a component of behavior was once the exclusive province of psychology. Currently, its study has been extended to include also the domains of molecular biology, pharmacology, and several clinical disciplines: neurology, psychiatry, and anesthesia. Psychopharmacology research, the study of the psychological effects of drugs, is at its best when it is conducted by multidisciplinary teams with expertise in psychology, pharmacology, and medicine. Given the massive and rich literature on memory and the exponential proliferation of publications examining the effects of drugs on memory, one would expect the facts, theories, and methodologic issues of the investigations to be brought together in one review, but this has not been completed. There are at least two reasons for this oversight.First, the dilemma of jargon and memory nomenclature intimidates the novice. 1Psychologists use many ways to describe the same phenomena based on their theoretical predisposition, resulting in a seeming myriad of terminologies, which can be confusing. For example, are there differences between short-term memory, primary memory, immediate memory, and working memory? Psychologists also use different models of memory to account for experimental data both qualitatively and quantitatively and different tasks according to their subareas, e.g. , experimental psychology or clinical psychology. Contrasting terms are used to describe various memory processes without drawing correlations among the various concepts. For example, what is the relation between implicit versus explicit learning and episodic versus semantic memory (concepts developed by experimental psychologists), and how do they relate to the Wechsler memory scale, the Bushke task, or the Rey auditory verbal learning test (used by clinical psychologists)? The second reason for the lack of a comprehensive review is that clinicians and pharmacologists are seldom familiar with assessments of memory and the choice and implications of the appropriate tests. They often get the erroneous impression that a complex mental function such as memory, with its individual variability and its well-known frequent failings, such as absentmindedness, distortions, and blocking, would not be susceptible to good research or yield reliable data. Studies by anesthesiologists, who were interested in finding premedicants, which suppress memory of their patients, were generally viewed as uncontrolled anecdotes unlikely to help in analysis of this mental function. Studies conducted in animals using chemicals were overlooked by most psychologists because of their unfamiliarity with the pharmacologic sciences. Thus, it came to pass that although the history of effects of drugs on memory is as old as the history of research on memory itself, it is only recently that psychologists have begun to notice the intellectual possibilities in this type of research. 2–4This article tackles some fundamental and basic issues about learning and memory and their interactions with drugs. It examines such topics as aims of research on the subject, assessment of memory, and specific methods in the design of studies. It emphasizes the how and why rather than reviewing and cataloging the effects of each drug or groups of drugs on memory. This article is meant to appeal to a broad readership without expertise in the psychology or psychopharmacology of memory. The first goal is to provide such readers with general information about memory and its psychopharmacology. The second goal is to make such readers more informed “consumers” of research on drugs and human memory so that they will be able to evaluate research claims in terms of soundness of the methods used to generate the data. The third goal is to assist the novice investigator in planning and conducting experiments and to give other readers the opportunity to consider research in this area as a worthwhile part of their careers.The German psychologist Ebbinghaus in the 1880s started the objective and quantitative study of memory 5(table 1). He invented the notion of nonsense syllables (such as BIK, QEH) as standardized, homogeneous test items. He learned lists of these items by reading them aloud and then tried to recite them from memory at various time intervals afterward. Through experimenting on himself, Ebbinghaus introduced many important ideas and methods about memory. One of his key contributions is the provision of the prototype for memory research. The current memory experiment consists of three phases: (1) a study or encoding phase in which material is presented to the subject; (2) a retention interval; and, finally, (3) a test or retrieval phase in which the subject attempts to respond to a question, the answer to which involves the use of the initially studied information. Research strategies have consisted largely of variations in the conditions for each phase. 6The Russian physiologist Ivan Pavlov 7discovered classic conditioning (1927), an associative learning procedure in which two different kinds of events are temporally paired with one another. For example, a dog may come to associate the sound of a bell and the presentation of food so that it salivates when the bell sounds, even in the absence of food. The dog has learned that the bell predicts the food’s presentation.The American psychologist William James 8made a sharp distinction between short-term (STM) and long-term memory (LTM). STM lasts seconds (which can be extended to minutes with active rehearsal), as when one looks up a telephone number and then holds it in mind for a few moments until he dials it. By contrast, LTM can last weeks, months, or even a lifetime and involves reaching back into the past. 9In the late 1960s, Atkinson and Shiffrin 10published a widely quoted article that described the two memory systems in more detail (fig. 1). The STM system receives information from sensory registers (e.g. , visual, auditory, olfactory, gustatory). Continued rehearsal determines whether the contents of the STM would be transferred to the LTM or would be lost by entry of new information. LTM is viewed as a permanent store in which information may be maintained indefinitely or may be subject to autonomous decay. This contrasts with STM, the temporary store of very limited capacity that stores information in a shallow or nonmeaningful format, such as the sound or articulation of the item (fig. 2). In addition to the description of these two systems or stores, several processes were also described. Encoding represents the first stage of mnemonic processing when information is encountered. Sensory stimuli are converted into a form that can be placed into memory and the material is acquired or learned. Consolidation is an intermediary stage; a durable permanent memory trace is formed through gradual reorganization where it can be stored or retained. Retrieval , the process of bringing information out of storage to be recalled or remembered, is the final stage of memory.Tulving 11made a distinction between two types of LTMs:episodic memory , which is memory for particular times and places, and semantic memory , which is memory for facts that a person has built up over the course of his or her life. So, for example, a question such as “What did you eat for dinner last night?” relies on retrieval from episodic memory, whereas a question such as “What kind of meat do you prefer?” relies on retrieval from semantic memory. Episodic retrieval may be accompanied by a type of awareness called autonoetic (self-knowing) awareness . The recollection of a particular time and place of the first accident when driving a car, for example, is infused with emotions, thoughts, and feelings of reexperience of a moment from the past. Semantic memory, by contrast, is characterized by noetic (knowing) awareness only. There is no feeling of reliving any previous episode when the fact that 100 cm is equivalent to 1 m is recollected. 12,13Tulving 14later introduced a third system, procedural memory , or memory for perceptual, motor, and cognitive skills. Schacter, a student of Tulving, developed another dichotomy in LTM 15between explicit and implicit memory (fig. 3). Explicit (or conscious or declarative ) memory refers to the intentional or conscious recollection of previous experiences, such as the details of an appointment to visit with a friend, as assessed by tests of recall or recognition (also called explicit or direct tests because reference is made to the study phase during testing). Implicit (or unconscious or nondeclarative ) memory , by contrast, refers to changes in performance or behavior that are produced by previous experiences on tests that do not require any intentional or conscious recollection of those experiences (the tests are called implicit or indirect tests because no reference is made to the study phase). 16The motor skill of riding a bicycle might have been learned years ago, and some things about the first experience might be remembered. However, the ability to ride even after years of nonuse is independent of any conscious recollection of that experience or ability to describe the skill. (It should be noted that although many authors use the term procedural memory to imply the memory subsystem concerned with learning and retention of motor skills, others use the term as synonymous with implicit memory.)Also in 1974, Baddeley and Hitch 17proposed an alternative to the STM store, using the term working memory . It consists of three components capable of both storing and manipulating information: a phonologic loop for the maintenance of verbal information (such as spoken words and meaningful sounds), a visuospatial sketch pad for the maintenance of visuospatial information (such as faces and spatial layouts), and a central executive for attentional control. The central executive component has been postulated to integrate the two slave systems, link them with information from LTM, and manipulate the resulting representation. Over the years, however, there were data that did not fit readily into this framework. 18For example, the memory span for sentences tends to approximate 16 words, in contrast to a span of approximately 6 for unrelated words. Therefore, Baddeley 19recently suggested a fourth component, namely the episodic buffer . It is assumed to act as a temporary storage system capable of holding information from the slave systems of working memory to be integrated with and linked to LTM. It is controlled by the central executive, using conscious awareness as a major retrieval strategy (fig. 4).We will use the terms STM and working memory as synonymous for simplicity in this review, despite the distinctions between the underlying models that have been cited previously. The reader should also note that STM may refer in the animal learning literature to later components of memory, up to the time of the establishment of stable LTM.Eric Kandel, the American neurobiologist, 20started working on the molecular mechanisms of memory in the 1970s that culminated in his award the Nobel prize in the year 2000 for discovering the central role synapses play in learning and memory. He used a simple experimental model, the sea slug Aplysia, combined later with work on mice. He showed that weak stimuli give rise to certain chemical changes in synapses, and these changes are the basis for STM. In contrast, stronger stimuli cause structural changes in both presynaptic and postsynaptic cells, associated with the growth of new synaptic connections or retraction of preexisting ones, which are the basis for LTM.The notion that drugs affect memory is as old as the history of the systematic study of human memory and is concerned in its early stage almost exclusively with nitrous oxide (table 1). Sir Humphrey Davy described the effect of the gas on memory in 1799 (cited in Cherkin and Harroun, 1971). 21John Snow 22reported the amnesia associated with the inhalation of diethyl ether in 1848. Davidson reported in 1925 the first controlled experimental investigation of a drug on memory and cognition using nitrous oxide 23and acetylene. 24Both chemicals impaired memory, and the impairment was related both to the difficulty of the memory task and to the concentration of the drug administered. McKinney 25(1932) and Marshall 26(1937) advocated the use of nitrous oxide to study the psychology of memory. Steinberg et al. 27–29extended these early findings in a series of studies in the 1950s. Nitrous oxide produced temporary amnesia by impairing the ability to store new information and therefore reduced interference with information learned before drug administration. The method of administration of the drug and its dose were identified as important factors. Clinical reports by anesthesiologists, specifically Dundee et al. 30and Hardy and Wakely 31in the 1960s on the amnesic properties of different premedicants, identified the benzodiazepines and scopolamine, which later became the most widely investigated drugs in relation to memory.In the 1970s, there was a resurgence of psychologically oriented or theoretically motivated studies of drug effects over a wider and more sophisticated scale. In a large series of studies, Ghoneim et al. 32–42tested the effects of benzodiazepines, scopolamine, opioids, propranolol, subanesthetic concentrations of nitrous oxide, ketamine, surgical anesthesia, marijuana, polydrug abuse, caffeine, and other drugs. These and other studies provided a detailed analysis of drug effects on memory and supplied converging evidence for its theoretical constructs. The history of learning and memory for events during anesthesia is as old as the history of anesthesia itself. Early observations by Cheek 43(1959), Wolfe and Millett 44(1960), and Levinson 45(1965) in anesthetized patients preceded the reports of what we now know as implicit memory by Warrington and Weiskrantz 46(1968) and Milner et al. 47(1968) in amnesic patients and the distinction between implicit and explicit memory 48(1985). (For reviews, see Ghoneim. 37,38) Studies in this area have important clinical significance as well as theoretical relevance for investigating the role of consciousness in memory. (For more reviews of the history of drugs and memory, see Polster 3and Curran 49). Table 1shows the overlap between the history of memory research and the action of drugs on memory.The measurement of both therapeutic and adverse effects of drugs on memory and their mode of action is important as part of the evaluation of existing and newly developed drugs and finding new brain-targeted therapeutics. 50Some drugs, e.g. , anesthetics, anxiolytics, sedative-hypnotics, antidepressants, and neuroleptics may impair memory, whereas others hold some hope of improving it. If amnesia is produced, it may be therapeutically desirable or essential, as in the practice of anesthesia, or it may be an undesirable side effect of treatment, as in therapy of anxieties, insomnia, depression, epilepsy, and schizophrenia. Memory and cognitive impairments in patients taking these drugs may endanger them and the public and may cause serious occupational difficulties by affecting job performance and quality of life. 51–55Such impairments may also cause legal difficulties arising from not recalling one’s actions. 56Elderly patients taking several psychoactive drugs can experience confusion and memory loss, pseudodementia , which may be misdiagnosed as organic dementia. Researchers usually study the types of memory and cognition affected, the magnitude and duration of the effects, and drug–drug and drug–disease interactions.Some drugs may mimic alterations in memory produced by diseases. For example, the pattern of memory impairment produced by has been suggested to be to that in and effects have been to that in and to with e.g. , ketamine, cognitive and to those of and drugs may therefore provide pharmacologic models of these which can be used to evaluate new drugs to or cognitive impairment associated with these before their use in and in These models may also help in understanding the mechanisms of because the molecular mechanisms of many of these drugs are (table 2). However, drug models have two (1) of the memory effects of drugs with their effects, which is important because patients with organic usually do not have or and (2) of the of memory impairment produced by the drugs with the of by e.g. , impairment of memory in although it is by the of memory is the most sophisticated and It is to the strategies of cognitive psychology with those of to the of a very complex mental function such as learning and memory. The of knowledge at the and and with detailed studies of learning and memory as a behavior to be the most Memory is one of the few mental processes that has such comprehensive research. The of studies that are to a account of memory is in The of using drugs as to study behavior and its is not the study of has been a rich of about function in and medicine. drugs that memory act through specific and and some act through and of changes in function, which in a in memory Therefore, one should be able to the events that to a certain in a specific type of of drug research is the fact that many of the studies conducted by psychologists in often on conditions to types of that are impaired in For example, are presented with stimuli conditions to the between explicit and implicit The lack of of such an is by the of the implicit because of the difficulty of that are of the information to be learned. of or a alternative for the relation between memory and provided that the of awareness can be to its The effects of the of consciousness by the dose of drug is another of many (table drugs have not their of knowledge about learning and memory. They have only provided converging evidence of existing the reason is that drugs are they to affect other than those which they are and there are interactions among the different However, the therapeutic of The of the pharmacologic functions of such as and that the or and the use of that strategies for new types of drugs. We that drug studies will be an important to other studies that memory and will help to generate and a of memory that memory into various each associated with some brain and It should be however, that memory function is a and a number of the same brain are in systems, as will be in the on The various e.g. , of consciousness and contents The systems in the have been with the of a subsystem of implicit memory. is a in the ability to or an item as a of a specific previous with the For example, are presented with a of words the . a retention the would be by the to the . is or to it from another two of associative previous presentation of the ) and previous presentation of of the the should be noted that there are to the memory systems has been in this The a processing that on specific or component processes during encoding and which are by specific example, the more or information is the more well it will contrasts with the on the and capacity of brain for specific tasks that are postulated by memory system It is that both the systems and processing are rather than we encoding is the process of sensory stimuli into a form that can be placed into memory, , a memory trace and new information are learned or Consolidation is the process of a durable record of what has been STM is converted to LTM, in storage from the of the brain to the where the new information is and there is of new retrieval is the process of bringing information out of storage to be recalled (fig. is between learning and memory. It is to of learning and memory as two and and retention are not synonymous with learning and memory, but both are to that learning or memory has when we of we place major on the investigation of the of we study memory, we are on the of However, for learning to be some new information be acquired and until for memory to be some information first be distinction of memory that is related to the memory processes is the between and or amnesia refers to to new which is by impaired memory of material presented after drug or of brain amnesia refers to an absence of memory for information and events before drug or of brain to the amnesia and amnesia for that were acquired before the but not to the cause whereas and treatment of animals with of cause a of amnesia by with the phase of memory processes is retrieval . The notion is that retrieval on the conditions the of the person or the feeling when information was learned. these conditions should be at encoding and retrieval to their may the of information. Thus, have been to recall a number of words when they were in the same in which they studied than when they were in a different learned when with in the same as with a However, the of in has been rather although it is a finding in the animal can be in many but most experimental studies have used a may use verbal or are most often used and include words, and There are data on of words such as of and which of the that have been used include of of simple of and learning motor skills. memory is to verbal memory. suggested that are more to be and stored in two independent verbal and also generally stronger effects in studies. to be different brain mechanisms underlying and is recognition performance with than recognition to be susceptible to presentation of verbal may be auditory or presentation tends to give a over the last few items of the may also be in drug studies because until of consciousness and effects of some drugs, e.g. , may with It is the only that can be used in studies of memory during are (or should theoretically and based on or about the of memory and the of memory systems, and In addition to their assessment these tests should provide the on which and have been 6The of any theoretical account of memory is based on the and with which that of memory can be in the tests to be both and of are A of memory tests components memory systems, or processes is in is based on the psychopharmacology literature rather than on memory For the the components of the would be to the of the tests for this type of memory and in addition to the capacity of STM. This capacity tends to be very on the of or two items. are presented with the items and then to recall them The immediate recall and the number of items presented make it an STM We use two (1) memory span for , which the capacity of the phonologic and (2) memory span for spatial , which the capacity of the visuospatial sketch attentional of the central executive may be assessed by a task that a recall of of with performance of a visuospatial