Korsakoff's syndrome

Severe Brain Dysfunction

In 1970, Richard Nixon was president of the United States of America, and Mr. F. was a 52-year-old patient residing permanently in a VA hospital in Massachusetts. Nixon had succeeded Lyndon Johnson who, after 5 years as president, declined to run again, in part because of his unpopularity regarding the ongoing, highly controversial war in Vietnam. Mr. F. was a veteran of World War II and had been stationed in Europe with the Air Force during the 1940s. His primary job had been to fuel airplanes. During Mr. F.'4s wartime service, Franklin Roosevelt had been president (1933-1945), and Harry Truman was elected subsequently to serve two terms in office (1945-1953). Mr. F. had been a heavy drinker, and after World War II was over, he continued to drink heavily, often without eating much food. In the 1960s, after bouts of heavy drinking, Mr. F. often was found to be disoriented, confused, and unable to care for himself. He eventually was hospitalized at the VA Hospital in Brockton, Massachusetts, with diagnoses of alcoholism and organic brain syndrome (a general term for acquired brain damage with abnormal behavioral consequences). Mr. F. became a permanent resident at the Brockton VA Hospital, and he remained sober from that time.

In December 1970, Mr. F. was transferred to the Boston VA Hospital for several weeks of observation, including complete physical and psychological evaluations. His IQ was normal, but his memory was not. Two weeks in o his long stay at the Boston VA medical facility, the following interview (reproduced only in part) took place between Dr. Nelson Butters, a noted expert on brain functions, and Mr. F.:

Doctor: What hospital are you in right now?

Mr. F.: I don't know. I'd say Brockton.

Doctor: This one here?

Mr. F.: Yeah.

Doctor: Right now?

Mr. F.: I don't know, but I'd say Brockton.

Doctor: Brockton?

Mr. F.: Yeah.

Doctor: This is the Boston VA Hospital. How long have you been here?

Mr. F.: I don't know. I'm just coming to.

Dotor: "Just coming to." Do you remember about 2 minutes ago I told you hw long you've been here in this hospital and what hospital you are in?

Mr. F.: No, I don't remember.

Doctor: I'll tell you again, okay?

Mr. F.: Fine.

Doctor: This is the Boston VA Hospital, and you've been here 2 weeks. Before you came here you were at the Brockton VA Hospital.

Mr. F.: I see. Thank you.

Doctor: Do you know who the president of the United States is?

Mr. F.: (Pause) Truman?

Doctor: Truman. And who was president before Truman?

Mr. F.: Let's see. Roosevelt.

Dotcor: How's Truman doing now? Doing pretty well?

Mr. F.: I haven't been up on, uh, current events, no.

Doctor: Are we in a war now? Are we involved in a war?

Mr. F.: We usually are.

Doctor: What war are we involved in?

Mr. F.: Let's see. (Pause) Asiatic war.

Doctor: What country are we fighting?

Mr. F.: Hmm. (Pause) So help me, I don't know.

Doctor: Were you in World War II?

Mr. F.: Yeah.

Doctor: What countries did you fight in Europe?

Mr. F.: I didn't fight. I was in theAir Force.

Doctor: I see. And what did you do then?

Mr. F.: Fueled airplanes. Refueled them.

Doctor: What country?

Mr. F.: Well, I was in England, France, and Germany.

Doctor: And who is president of the United States now?

Mr. F.: Truman.

Doctor: Was John Kennedy ever president?

Mr. F.: No. (Pause) Was he? Was he president? I'm not sure now whether he was or not. . . .

Doctor: What hospital are you in right now?

Mr. F.: I don't know. I'm just coming to.

"In 1976, Dr. Butters again interviewed Mr. F.; Gerald Ford was president, and the Vietnam War was over. Dr. Butters asked many of the same questons he had asked Mr. F. 6 years earlier, and Mr. F. gave many of the same answers. Here is a brief excerpt from the 1976 interview:

Doctor: Do you know who the president of the United States is?

Mr. F.: Let's see, uh....

Doctor: The president of the United States.

Mr. F.: Truman?

Doctor: Truman. Well, Truman goes back quite a while ago. There must be someone else.

Mr. F.: Eisenhower?

Doctor: Uh-uh. Who else? Who is president right now?

Mr. F.: Beats me.

Doctor: Beats you. Okay, let me give you some hints, okay? He used to be a congressman from Michigan. Does that help you?

Mr. F.: No.

Doctor: Okay, let me give you another hint. His last name begins with the letter "F." Okay, who do you think it might be?

Mr. F.: I haven't the vaguest idea.

A few minutes later:

Doctor: Are we at war now?

Mr. F.: I think that Korea war's all over.

Doctor: The Korean war's all over, right; Korea's all done, okay. . .and what war did you fight in?

Mr. F.: Two. World War II. I didn't fight. I was an, uh, observer. I was in the Air Force ground troop.

"Mr. F. has amnesia. Amnesia, especially anterograde amnesia, or memory loss for recent events, is an intriguing but serious consequence of long-term alcohol abuse generally associated with the label "Korsakoff's syndrome." Patients with Korsakoff's syndrome are permanently unable to remember new information for more than a few seconds. In the above example, Mr. F. could not remember the name of the hospital to which he was transferred, when he was admitted, nor the reason for his hospitalization. Past memories, compared with new memories, are relatively well preserved. It is clear that Mr. F. remembered his Air Force service, the presidents during that time in his life, and even--vaguely--the name of the Brockton VA Hospital where he had resided for nearly a decade.

Because events are forgotten a few seconds after they occur, virtually nothing new is learned, and the patient with Korsakoff's syndrome lives in the past. The amnesia is thought to be cause indirectly by nutritional deficiencies, and directly by the toxic effects of alcohol on the brain.

S.S. Korsakoff was a 19th century Rusian physician who obsrved patients with widespread brian damage from alcoholism and other causes (e.g., nutritional deficiencies, severe and prolonged gastro-intestinal disturbanceS, and toxemia in pregnancy). He wrote:

The disorder of memory manifest itself in an extraordinarily peculiar amnesia, in which the memory of recent events, those which just happened, is chiefly disturbed, whereas the remote past is remembered fairly well. . . .This reveals itself primarily in that the patient constantly asks the same questions and repeats the same stories. At first, during conversation with such a patient, it is difficult to note the presence of psychic disorder; the patient gives the impression of a person in complete possession of his faculties; he reasons about everything perfectly well, draws correct deductions from given premises, makes witty remarks, plays chess or a game of cards, in a word, comports himself as a mentally sound person. Only after a long conversation with the patient, one may note that at times he utterly confuses events and that he remembers absolutely nothing of what goes on around him: he does not remember whether he had his dinner, whether he was out of bed. On occasion the patient forgets what happened to him just an instant ago: you came in, convered with him, and stepped out for one minute; then you come in again and the patient has absolutely no recollection that you had already been with him. Patients of this type may read the same page over and again, sometimes for hours, because they are absolutely unable to remember what they have read... With al this, the remarkable fact if that, forgetting all events which have just occurred, the patients usually remember quite accurately the past events which occurred long before the illness. What is forgotten usually proves to be everything that happened during the illness and a short time before the beginning of the illness. [1]

While in the hospital, Mr. F. was given a careful neuropsychological evaluation consisting of tests of memory, perception, attention, problem-solving ability, and other intellectual functions. From the results, it became clear that his original diagnoses could be refined to the single diagnosis of alcoholic Korsakoff's syndrome. This diagnosis had not been considered initially, probably because the syndrome is uncommon and because the scientific literature on Korsakoff's syndrome in the 1960s was very limited (with only a few papers having been published on the subject, e.g., Meissner 1968, and Talland 1965).

Mr. F.'s amnesia was severe and permanent. In addition, he was unaware and unconcerned about the extent of his disability, and he thought he was hospitalized because, "Maybe something happened to my mother." Mr. F. is not unique. His tragic condition is an example of one of the possible legacies of long-term chronic alcoholism.

INCIDENCE OF SEVERE

BRAIN DAMAGE RELATED

TO ALCOHOL ABUSE

Alcohol can damage the brain in many ways. The brain is vulnerable to the toxic effects of alcohol itself and can be affected by alcohol-related damage to other organs, including the liver, pancreas, and heart (see the article by Arria et al., pp. 112-117). Brain damage may also result from head trauma caused by falls or other accidents occurring under the influence of alcohol. Finally, poor dietary habits accompanying chronic intoxication can lead to nutritional deficiencies that can damage the nervous system.

The type and severity of brain damage linked with alcoholism can vary depending upon a large number of influences, including genetic and prenatal vulnerabilities, age of onset of drinking, type and amount of alcohol consumed, and diet.

Although statistics on the prevalence of alcohol-related brain damage vary, the incidence of alcohol-related organic brain syndrome is approximately 10 percent of adult dementias in the United States (Martin and Eckardt 1985; Wells 1979). In the acute phase, Korsakoff's syndrome occurs together with Wernicke's encephalopathy; the diagnosis at this stage is Wernicke-Korsakoff's syndrome. Wernicke's encephalopathy refers to alcohol-related brain degeneration characterized behaviorally by general confusion, abnormal gaze and galt, and incoherent speech (Victor et al. 1971). With abstinence and vitamin supplementation (chiefly with the B vitamin thiamine), the encephalopathy clears. However, in approximately 25 percent of patients with acute symptoms of Wernicke-Korsakoff's syndrome, anterograde amnesia persists and is irreversible (Dreyfus 1979; Victor et al. 1971). Korsakoff's syndrome alone, with anterograde amnesia as the symptom standing in sharp contrast to other cognitive deficits described below, is not a common condition; one estimate of its frequency is approximately 10 per million (0.001 percent) of first psychiatric admissions (Centerwall and Criqui 1978).

Some researchers have found evidence of a possible genetic component, or inborn predisposition, to Wernicke-Korsakoff's syndrome. The evidence revolves around the demonstration of an enzyme deficiency in these patients, thought to be inherited, such that their bodies cannot metabolize thiamine efficiently (Blass and Gibson 1977; Dreyfus 1979). In animals, thiamine deficiency can lead to brain damage and memory impairments (Markowitsch and Pritzel 1985; Witt and Goldman-Rakic 1983). Therefore, individuals with a metabolic disorder that does not permit normal use of thiamine, or who do not eat enough thiamine-containing foods, are at risk for developing brain lesions associated with Wernicke-Korsakoff's syndrome. (Genetic components of alcoholism are discussed in a later section.)

BRAIN SYSTEMS IMPLICATED IN

ALCOHOLIC KORSAKOFF'S SYNDROME

Anterograde amnesia, whatever the cause, results from damage to brain regions essential for normal memory. The brain regions typically associated with the ability to form new memories can be seen in Figure 1. These regions include portions of the limbic system, a complex of interconnected structures located deep inside the brain as well as in the temporal lobes bilaterally. Limbic structures important for normal short-term memory include the hippocampus and amygdala (Mishkin and Appenzeller 1987). Also important for memory are parts of the diencephalon, a division of the brain nestled within the limbic system directly above the brainstem (Talland and Waugh 1969; Victor et al. 1971); and the basal forebrain, located just in front of the diencephalon (Arendt et al. 1983).

The Hippocampus and Amygdala

The role of the hippocampus in human memory has been recognized for decades. Bilateral removal of the hippocampus (along with other parts of the temporal lobes) to control intractable epilepsy has left patients with severe anterograde amnesia similar to that seen in patients with alcoholic Korsakoff's syndrome (Scoville and Milner 1957). (These patients generally do not exhibit the additional cognitive deficits of Korsakoff's syndrome, presumably attributable to diffuse cortical atrophy, as discussed below.) Although recent studies of hippocampal function have refined and broadened our understanding of the role of the hippocampus in behavior, its importance in memory still is generally accepted.

The role of the amygdala in memory has not been established so definitively. The amygdala receives fibers from other brain regions involved in processing information from the senses (Turner et al. 1980). In turn, the amygdala projects information to other brain regions, including the same primary sensory areas from which it receives information (Mufson et al. 1981). The association of stimulus and reward, a key ingredient in learning (Bower and Hilgard 1975), is thought to converge in the amygdala (Mishkin 1982; Murray and Mishkin 1985). A recent study of cross-modal functions in alcoholics has disclosed deficits in patients with Korsakoff's syndrome. Cross-modal functions include the ability to use information from one sensory modality (e.g., vision) to help with a second modality (e.g., touch). Deficits in these functions suggest damage to the amygdala (Oscar-Berman et al. in press b).

The Diencephalon

There is controversy about the precise role of diencephalic damage in amnesia (Butters and Stuss 1989), although the involvement of this region has been documented clearly (e.g., Victor et al. 1971). The main diencephalic structures that have been implicated are the mammillary bodies of the hypothalamus, the dorsomedial thalamic nucleus, and the nerve fibers connecting these two structures (Figure 1). These structures have been singled out because of their anatomical relationship to the hippocampus and amygdala, and because autopsy has revealed damage there in many memory-disorder patients (Butters and Stuss 1989). For example, patients with acute alcoholic Wernicke's encephalopathy who do not receive thiamine treatment may show evidence of hemorrhagic lesions in the region around the diencephalon. In addition, amnesia has been associated with damage to these diencephalic structures following trauma, stroke, or tumor (Butters and Stuss 1989).

The Basal Forebrain

Damage to the nuclei of the basal forebrain, including the nucleus basalis of Meynert and adjacent sites, has been linked to memory disturbances in several neurological conditions such as Alzheimer's disease, ruptured anterior communicating artery aneurysm, and alcoholic Korsakoff's syndrome (Arendt et al. 1983; Damasio et al. 1985; Gade 1982; Phillips et al. 1987). The nucleus basalis of Meynert sends fibers to various regions, including the hippocampus and cerebral cortex, and is considered important for normal memory functions (Mesulam and Mufson 1984). The nucleus basalis of Meynert also is a major source of the important neurotransmitter acetylcholine, which will be discussed later.

The Cerebral Cortex

In patients with alcoholic Korsakoff's syndrome, damage is not restricted to the brain regions typically associated with short-term memory. Rather, the damage is widespread, and is thought to involve large regions of the cerebral cortex as well. The type and extent of cortical damage can be determined by close examination of the nerve cells themselves (neuropathological evidence) and by using techniques that allow the brain to be viewed inside the skull (neuroradiographical evidence). Such procedures reveal a widening of the sulci (grooves on the brain's surface) and enlargement of the ventricles (fluid-filled cavities deep inside the brain); these changes suggest cortical atrophy (N. Butters and T. Jernigan, personal communication, July 24, 1989; Cala et al. 1978).

Patients with Korsakoff's syndrome also exhibit clinical signs associated with damage to the frontal cortex, including emotional apathy and perseveration, or the abnormal constant repetition of a response (see Butters et al. 1987; Moscovitch 1982; and Oscar-Berman 1980, 1984, for reviews). Deficits suggestive of bilateral temporal cortical atrophy also have been reported, such as difficulty in forming visual associations (Oscar-Berman and Zola-Morgan 1980b). Diffuse damage to cortical regions also is considered responsible for such cognitive deficits as poor attention, retarded perceptual processing, and disinhibition (Ellis and Oscar-Berman 1989; Oscar-Berman 1980, 1984). In patients with alcoholic Korsakoff's syndrome, these additional cognitive deficits are intertwined with--and contribute to--the anterograde amnesia that is the hallmark of their disease.

In alcoholics who do not develop Korsakoff's syndrome, cortical atrophy also is prevalent (Lishman 1981; Wilkinson and Carlen 1982) and may be directly responsible for diverse cognitive changes. Among these are deficits in visuospatial functions, or the ability to deal with objects in two-dimensional or three-dimensional space. These functions can be assessed in many ways (see the article by Cermak, pp. 130-136); a common method is to use performance subscales of IQ tests, which include such tasks as substituting symbols for numbers, assembling small jig-saw puzzles, or arranging colored cubes according to instructions.

The Right Hemisphere Hypothesis

Like alcoholics, patients with damage to the right side of the brain caused by stroke, trauma, or tumor also perform poorly on visuospatial tasks. By contrast, such patients, and alcoholics as well, perform normally on verbal subscales of IQ tests. Verbal IQ depends heavily upon language skills and is considered to be more closely tied to the left than to the right side of the brain. Consequently, many alcohol researchers suggest that the right half of the brain might be more vulnerable to the effects of alcohol abuse than the left half of the brain (see Ellis and Oscar-Berman 1989 for review). This possibility was known as the right hemisphere hypothesis. According to this hypothesis, alcohol selectively disrupts right hemisphere functions such as visuospatial skills, while sparing left hemisphere functions such as language. The normal differentiation of functions between the right and left sides of the brain is referred to as brain asymmetry.

Anatomical and electrophysiological evidence regarding altered brain asymmetries in alcoholics is scarce. Dr. Henri Begleiter and his colleagues in New York performed electrophysiological investigations into event-related brain potentials (ERPs). ERPs are certain electrical impulses generated inside the brain, transmitted through electrodes placed on the scalp, and filtered and amplified by sophisticated computerized equipment. These investigators looked specifically at one ERP electrical component, the P3 component, because P3 is thought to reflect some aspect of a subject's evaluation of the importance of stimuli. Using ERP recordings, Porjesz and Begleiter (1985) found evidence supporting the notion of right-sided brain dysfunction in alcoholics: The P3 was found to be abnormal, especially over the right frontal region of the brain. Alcoholics also showed less asymmetry in the amplitude of electrical impulses than did nonalcoholic controls. Remarkably similar findings also have been obtained in subjects following acute administration of alcohol in intoxicating amounts. ERPs are discussed in further detail later in this article.

Direct behavioral tests of the right hemisphere hypothesis have led to conflicting findings. The most notable behavioral research (Ellis and Oscar-Berman 1989) has used tasks that cause competition between two sources of sensation--simultaneous dichotomous stimulation techniques. As a class, these techniques involve the delivery of information simultaneously to two separate sensory channels on the left and the right sides of the body (the two ears, the two hands, or the two visual half-fields). Under dichotomous condition, the right and left input channels compete with each other. Mainly because of the organization of the nervous system, the left side of the body responds faster and more efficiently than the right side to verbal information, and the opposite side works more is superior at processing nonverbal information.

In our laboratories in Boston, we administered numerous types of dichotomous tests, using three sensory modalities (hearing, vision, and touch), to alcoholics with and without Korsakoff's syndrome (Ellis and Oscar-Berman 1989). The majority of the findings from our experiments did not support the hypothesis that alcoholism affects right hemisphere functions differently than left hemisphere functions. In general, alcoholics did not show greater loss of nonverbal than verbal abilities, nor was one input channel compromised more than the other. With further research, we concluded that the early emphasis on defective nonverbal performance appeared to be an artifact of at least two features of the nonverbal tasks used: demands related to perceptual processing and demands related to formulating effective strategies to help with memory.

Most of the verbal tasks were simple and easily processed, and subjects tended to approach them with simple strategies. Nonverbal tasks used materials that were less familiar than words, such as shapes, slanted lines, and musical notes. These tasks took longer and required more elaborate strategies to be processed than the verbal tasks. When sufficient processing time was permitted, and when strategies were simplified in one way or another, alcoholics performed on nonverbal tasks as well as they performed on verbal tasks. It should be noted that perceptual processing relies heavily upon sensory and association regions of the cerebral cortex, and strategy planning has been linked to the prefrontal cortex. As mentioned earlier, cortical atrophy has been implicated in chronic alcoholism; new evidence from dichotomous stimulation experiments (Ellis in press) has challenged the right hemisphere hypothesis and supports the idea of symmetrical cortical damage.

Several authors have reviewed the literature relevant to differences in brain structure among alcoholic subgroups (Arendt et al. 1983; Butters and Granholm 1987; Wilkinson and Carlen 1982). Differences in brain function between alcoholics with and without Korsakoff's syndrome presumably are attributable to differences in the distribution and extent of brain pathology. Although both groups have considerable cortical pathology, their functional differences have been linked principally to the more extensive subcortical damage found in patients with Korsakoff's syndrome (mainly in limbic, diencephalic, and basal forebrain structures).

ALCOHOLISM AND AGING

Alcoholism among the elderly--although not as prevalent as in other age groups--is clearly a serious problem (National Institute on Alcohol Abuse and Alcoholism 1982). Wilkinson and Carlen (1982) compared radiological brain scans of alcoholics without Korsakoff's syndrome to those of nonalcoholic controls across five age decades. A striking characteristic of the brains of the alcoholics was abnormal ventricular enlargement and widening of the cerebral sulci. Of special interest was the fact that the ventricles and sulci became increasingly wider with increasing age. In the 1950s, Courville described this feature of cerebral atrophy in the brains of alcoholics, and likened it to the brain shrinkage that occurs with normal chronological aging (see Courville 1966). That is, alcoholics and normal aging individuals showed fairly uniform cortical atrophy, most prominent in the frontal lobes, and extending backwards to the parietal lobes (the top and sides of the brain above the temporal lobes). This finding also has been reported by others (Wilkinson and Carlen 1982; Wood and Elias 1982).

From the observed similarities in the brains of alcoholic and aging individuals sprang the search for parallels in functional decline associated with alcoholism and aging. The premature aging hypothesis (Parsons and Leber 1982; Ryan 1982; Ryan and Butters 1986) has been put forth in two versions. According to the first, the "accelerated aging" interpretation, alcoholism is accompanied by the precocious onset of neuroanatomical and behavioral changes typically associated with advancing age: Cognitively, or neuropsychologically, alcoholics become old before their time. The second version places the timing of the changes somewhat differently. In this view, which has been labeled the "increased vulnerability" interpretation, the aging brain is more vulnerable to the deleterious influences of toxic substances, including alcohol, than is the brain of a younger person. Therefore, the cognitive decline associated with normal chronological aging (beginning at around age 45) receives added momentum from the effects of alcohol abuse. This version predicts that older alcoholics will be more impaired than age-matched nonalcoholics; however, the same will not necessarily be true of younger alcoholics, since they will not have begun to manifest the changes associated with aging. Both forms of the premature aging hypothesis posit qualitative as well as quantitative parallels between certain neuropsychological changes due to aging and those due to alcoholism.

Does alcoholism cause premature aging, or do the behavioral consequences of aging and alcoholism merely mimic each other? So far, the literature relating the two types of pathological influence suggests that causality is unlikely (e.g., Ellis and Oscar-Berman 1989; Ryan and Butters 1986). In order to evaluate these hypotheses, we carried out a series of experiments on alcoholic and nonalcoholic men between the ages of 25 and 75, and studied their perceptual, intellectual, and cognitive abilities (reviewed by Ellis and Oscar-Berman 1989, and Oscar-Berman and Ellis 1987). Specifically, we looked for the differential effects of aging, alcoholism, and the interaction of aging and alcoholism on visual, auditory, and tactual perception, memory, and cerebral lateralization, or the asymmetrical functions of the two halves of the brain.

Results of our studies indicate that visual, auditory, and tactual processing and memory functions, and cross-modal associative functions were more severely disrupted by aging than by alcoholism. The compounded effects of aging and alcoholism were observed rarely, and whenever we did find even modest support for the premature aging hypothesis, it was only for the "increased vulnerability" version (Oscar-Berman et al. in press a,b). Consequently, the concept of aging as a model for the study of alcoholism may have to serve chiefly as a metaphor.

It should be noted that patients with Korsakoff's syndrome had the most profound deficits on the tasks we gave, their deficits being more severe than those of the oldest of the alcoholics without Korsakoff's syndrome (Oscar-Berman et al. in press a,b). Interestingly, Wilkinson and Carlen (1982) indicated that measures of cortical atrophy in patients with Korsakoff's syndrome were not age related, as they were in alcoholics without Korsakoff's syndrome. This may be because patients with Korsakoff's syndrome already have suffered maximal alcohol-related brain damage, such that age-related cortical cell loss becomes irrelevant. In any case, it is important in considering alcoholic populations (with and without Korsakoff's syndrome) to be able to differentiate, describe, and quantify the separate contributions of aging and alcoholism to cognitive decline.

NEUROTRANSMITTER DEFICIENCIES

When nerve cells communicate, they use chemical substances known as neurotransmitters to send messages. Abnormalities in brain neurotransmitter systems have been implicated in many neurological disorders. Two neurotransmitter systems in the brain that have been associated with neurological diseases involving memory dysfunction are the cholinergic system and the catecholaminergic system.

Deficiencies in the cholinergic neurotransmitter, acetylcholine, have been associated with memory loss in Alzheimer's disease (Kish et al. 1989), ruptured anterior communicating artery aneurysm (Arendt et al. 1983; Damasio et al. 1985; Gade 1982; Phillips et al. 1987), and Korsakoff's syndrome (Arendt et al. 1983; Joyce 1987). As mentioned earlier, an area in the basal forebrain, the nucleus basalis of Meynert, is a major source of acetylcholine; it communicates directly with various regions known to be important in memory and learning, including the hippocampus and cerebral cortex (Mesulam and Mufson 1984). In patients with Korsakoff's syndrome, there is a reduction in brain cholinergic activity, as well as cell loss in the basal forebrain area (particularly the nucleus basalis of Meynert) (Arendt et al. 1983).

The catecholaminergic system comprises a closely related group of neurotransmitter--dopamine, norepinephrine, and epinephrine. Three lines of evidence implicate the catecholamines in the memory loss of Korsakoff's syndrome (see Joyce 1987 for review). First, the areas of brain damage associated with Korsakoff's disease frequently involve the site of origin of the norepinephrine pathway, the locus coeruleus (Victor et al. 1971). Second, in patients with Korsakoff's syndrome, behavioral deficits have been related to reduced brain activity of two separate catecholamines, norepinephrine and dopamine (McEntee and Mair 1978; Mair et al. 1982, 1985). Third, although catecholamine levels are normal in samples of spinal fluid taken from patients with Korsakoff's syndrome, memory deficits can be reversed transiently by treatment with clonidine, a drug that increases norepinephrine levels (Martin et al. 1987; McEntee and Mair 1980).

Because it is not yet certain which neurotransmitters are critical for normal memory functions, it is difficult to implicate clearly the dysfunction of a particular neurotransmitter system in the amnesia of alcoholic Korsakoff's syndrome. however, the evidence just reviewed does suggest that the study of neurotransmitters may lead to successful psychopharmacological treatment of the symptoms.

ADDITIONAL DOMAINS OF

IMPAIRMENT IN FUNCTION

Although amnesia is the most clearly defined and described symptom of Korsakoff's syndrome, Talland (1965) and Meissner (1968) have pointed to the inaccuracy of the classical description of the problem: "The defect can only loosely be said to be a defect in memory. The basic defect extends to much more than simply memory functions, and leaves some memory functions untouched" (Meissner 1968, p. 6). Indeed, research on preserved memory capacities was a popular topic during the 1980s. Many investigators demonstrated that patients with Korsakoff's syndrome were able to remember some things ver well, such as general rules for solving problems. In the jargon of cognitive neuropsychology, patients with Korsakoff's syndrome were able to maintain relatively intact incidental, semantic, or procedural memory abilities, compared, respectively, to defective intentional, episodic, or declarative memory abilities (e.g., Cohen 1984; Graf et al. 1984; Jacoby 1984; Kinsbourne and Wood 1982; moscovitch et al. 1986). This means simply that patients with Korsakoff's syndrome could remember how to do many things without being aware of when and where they learned them; they also could remember rules of action (e.g., how to solve a puzzle) without remembering isolated steps or facts.

In addition, it is now known that impairments associated with Korsakoff's disease, as well as with alcoholism uncomplicated by severe amnesia, entail concurrent deficits in many aspects of neuropsychological functioning, most notably sensory processing, visuospatial abilities, arousal, and maintaining appropriate responses (see Ellis and Oscar-Berman 1989; Oscar-Berman and Ellis 1987; and Porjesz and Begleiter 1985, for reviews). The aforementioned functions rely heavily upon the integrity of the cerebral cortex. Descriptions of these neuropsychological deficits and their asociated areas of brain damage have been summarized by many authors, including Butters and Cermak (1980), Oscar-Berman (1980, 1984, 1987), Talland (1965), and Tarter (1975, 1976).

Abnormalities in the motivational and emotional functions were described by Korsakoff in his original papers (Victor and Yakovlev 1955). Patients with Korsakoff's syndrome were described as apathetic, anxious, irritable, and agitated. although apathy may be caused by prefrontal cortical damage (Oscar-Berman et al. in press a), many of the motivational and emotional changes in patients with Korsakoff's syndrome now are thought to be related to lesions in the limbic system (Satz and Heilman 1983). Like abnormalities in cortically based functions (such as perception and inhibition), abnormalities in limbically based functions (such as motivation and emotion) can have direct bearing on the ability to learn and remember new materials. If someone is only dimly aware of the relevance of a paticular item, or if some piece of information is seemingly unimportant, then that item or information may never be remembered.

One way of studying motivation is to ascertain whether (or to what extent) subjects are sensitive to available rewards. Although the exact role of reinforcement in the learning process is still a matter of debate (e.g., see Bower and Hilgard 1975, and Mackintosh 1983), there is general agreement that reinforcement facilitates the association of both internal and external stimuli with certain activities or responses, or with other stimuli.

The decreased responsivity of patients with Korsakoff's syndrome to changing reward contingencies has been studies (Oscar- Berman et al. 1983; Oscar-Berman et al. 1976; Oscar-Berman and Zola-Morgan 1980a,b; Oscar-Berman et al. 1982). All of these studies shared one important experimental characteristic: Positive reinforcement, which had been available for many trials in a specific, consistent, and regular pattern as a function of an individual subject's performance, was changed unexpectedly. The degree of a subject's "adjustment" to the changes in reward was the major dependent variable. In all cases, patients with alcoholic Korsakoff's syndrome--and alcoholics without Korsakoff's syndrome to a lesser degree--were slower to adjust than controls. In other words, alcoholism can reduce a person's sensitivity to rewards given for his or her own actions.

Begleiter and his colleagues (Porjesz et al. 1986) studied motivational changes in alcoholism by analyzing the P3 component of event-related brain potentials (ERPs). As discussed earlier in this article, the P3 component of the ERP is thought to reflect some aspect of one's subjective evaluation of the importance of a stimulus. the investigators employed an experimental task using simuli with differing degrees of value or importance to the subjects. they found that the P3 component was abnormal in many alcoholics; P3 voltages were reduced under several experimental conditions, suggesting deficits "in the motivational and cognitive systems of alcoholics" (p. 9). These results are consistent with the hypothesis that diencephalic, limbic system, or basal forebrain structures (which are directly or indirectly interconnected and important in motivational functions) are compromised with alcohol abuse (Arendt et al. 1983; Ryand and Butters 1986).

Motivational changes with alcoholism, including ERP abnormalities, are not specific to patients with Korsakoff's syndrome. however, P3 abnormalities have been found in young nondrinking sons of alcoholics at risk for developing alcoholism. It is possible, therefore, that the P3 deficits may precede alcoholism, or may be an electrophysiological marker for people susceptible to alcoholism. If so, the findings may also help to clarify the role of genetic factos in alcoholism and in alcohol-related brain damage.

In addition to motivational abnormalities, alcoholics with Korsakoff's syndrome display a spectrum of emotional or affective changes that is notably reminiscent of alterations seen in patients with lesions to the frontal lobes (Bear 1983; Lhermitte and Signoret 1976), or to the cortex of the right hemisphere (Satz and heilman 1983). Events that normally hold affective significance may elicit no emotional arousal in these patients, who, in addition, may generate little spontaneous emotionally oriented behavior. The disturbance is thus described as one of "inertia" of emotional processes. Interpersonally, these individuals leave an impression of dullness, apathy, and emotional flatness that may be mistaken for depression (Bedi and Halikas 1985; Lezak 1983; Lishman 1978). clinical descriptions abound with impressions of apathy and indifference in alcoholics (e.g., Overall et al. 1985).

Some commentators have considered these behavioral changes to be closely associated with the attentional abnormalities described earlier: What manifests as a lapse in active attentional/emotional involvement is, in turn, related to memory failure (Talland 1965). Although it would be difficult to confirm causality between disruption of emotional and attentional mechanisms, it certainly seems useful to consider them as part of a distinct behavioral cluster. Deficits in these combined functions might reflect the workings of a complex behavioral system comprising brainstem, limbic, and cortical elements--all of which have been implicated in attentional and mood disorders (Duyckaerts et al. 1985).

SUMMARY

When the acute phase of Wernicke's encephalopathy resolves, some patients are left with a devastating memory loss for recent events (anterograde amnesia) known as alcoholic Korsakoff's syndrome. Other neuropsychological changes occur as well, including deficits in attention, perception, motivation, and emotion. The amnesia is thought to be caused mainly by subcortical damage to structures in the limbic system, diencephalon, or basal forebrain; the additional neuropsychological changes probably reflect cortical dysfunction as well as limbic system damage. Abnormalities of cholinergic and catecholaminergic neurotransmitter systems also have been implicated in the impairments associated with Korsakoff's syndrome.

Alcoholics who do not develop Korsakoff's syndrome may exhibit some of the same nonamnesic symptoms as patients with Korsakoff's syndrome, but not nearly with the same severity. Similarities in deficits displayed by alcoholics with and without amnesia probably reflect overlap in the cortical regions affected by longterm alcohol abuse. Despite the prevalence of visuospatial deficits in alcoholics (and in chronologically aging nonalcoholic controls), the cortical atrophy does not appear to be greater in the right hemisphere than in the left. likewise, alcoholism does not seem to accelerate chronological aging. In contrast to some apparent similarities between alcoholics with and without Korsakoff's syndrome in behaviors reflecting cortical involvement, the differences in the patterns of impairments in amnesic and nonamnesic alcoholics have been attributed to differences in location and degree of damage to subcortical structures.

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MARLENE OSCAR BERMAN, PH.D., is professor of neurology and psychiatry, Boston University School of Medicine/School of Public Health, Boston, Massachusetts.

This work was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (AA07112), and by funds from the Research Service of the U.S. Department of Veterans Affairs.

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