Marlene Oscar-Berman

Alcohol: Effects on Neurobehavioral Functions and the Brain

Alcoholism results from an interplay between genetic and environmental factors, and is linked to brain defects and associated cognitive, emotional, and behavioral impairments. A confluence of findings from neuroimaging, physiological, neuropathological, and neuropsychological studies of alcoholics indicate that the frontal lobes, limbic system, and cerebellum are particularly vulnerable to damage and dysfunction. An integrative approach employing a variety of neuroscientific technologies is essential for recognizing the interconnectivity of the different functional systems affected by alcoholism. In that way, relevant experimental techniques can be applied to assist in determining the degree to which abstinence and treatment contribute to the reversal of atrophy and dysfunction.

Bilateral frontal lobe disease and selective delayed response deficits in humans.

The performance of patients with frontal lobe disease was compared with that of amnesic patients (with etiology of alcoholic Korsakoffs disease or surgically treated ruptured anterior communicating artery aneurysm) on tasks known to be sensitive to frontal lobe damage in nonhuman primates: delayed alternation (DA) and delayed response (DR). Alcoholic patients with no clinical memory impairment served as controls. Results showed that bilateral frontal lobe damage in humans is associated with impairment on both tasks. In addition, there was no relation between performances on DA and DR and performance on standardized tests of memory, a result strengthening the suggestion that the former tasks are not sensitive to anterograde amnesia in humans.

Relationship between dopaminergic neurotransmission, alcoholism, and Reward Deficiency syndrome.

In this review, we described the neural substrates underlying Reward Deficiency syndrome which, in turn, is posited to underlie alcohol dependency. Alcoholism is a complex, multifactorial disorder that results from the interplay between genetic and environmental factors. The D2 dopamine receptor (DRD2) has been associated with pleasure, and the DRD2 A1 allele has been referred to as a reward gene. Evidence suggests that there is a tripartite interaction involving dopamine receptor deficiency, a propensity to abuse alcohol, and reduced sensitivity to rewards. This interaction relies heavily on genetic characteristics of the individual, with certain ethnic groups having a greater tendency toward alcoholism than others. The DRD2 has been one of the most widely studied in neuropsychiatric disorders in general, and in alcoholism and other addictions in particular. The dopamine D2 (DRD2) gene, and especially its allele TaqI A1 allele and its receptor, also may be involved in comorbid antisocial personality disorder symptoms, high novelty seeking, and related traits. The mesocorticolimbic dopaminergic pathway system plays an especially important role in mediating reinforcement by abused drugs, and it may be a common denominator for addictions such as alcoholism. When the mesocorticolimbic dopamine reward system dysfunctions (perhaps caused by certain genetic variants), the end result is Reward Deficiency syndrome and subsequent drug‐seeking behaviors. Reward Deficiency syndrome refers to the breakdown of the reward cascade, and resultant aberrant conduct, due to genetic and environmental influences. Alcohol and other drugs of abuse, as well as most positive reinforcers, cause activation and neuronal release of brain dopamine, which can decrease negative feelings and satisfy abnormal cravings. A deficiency or absence of DRD2 receptors then predisposes individuals to a high risk for multiple addictive, impulsive, and compulsive behaviors. Although other neurotransmitters (e.g., glutamate, gamma‐aminobutyric acid (GABA), and serotonin) may be important in determining the rewarding and stimulating effects of ethanol, dopamine may be critical for initiating drug use and for reinstating drug use during protracted abstinence. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148‐7299:1/suppmat/index.html.

Memory deficits in Alzheimer's patients: a comprehensive review.

Despite considerable experimental work on Alzheimers disease (AD), the underlying cognitive mechanisms as well as the precise localization of neuropathological changes critical for memory loss remains undefined. A review of the neuropsychological literature on long-term memory deficits in AD patients suggests that AD patients display (a) a pervasive deficit of explicit memory, (b) a partial deficiency of implicit memory for verbal and visuoperceptual material (as measured by repetition priming procedures), and (c) a substantial sparing of implicit memory for visuomotor skills. The explicit memory loss is likely a result of encoding as well as consolidation difficulties. A faulty lexical-semantic knowledge structure appears responsible for deficient repetition priming effects. Since neuropathological changes diffusely affect the brain of AD patients, establishing a clear relationship between localization of cerebral lesions and memory deficits is particularly difficult. Nevertheless, data suggest that extensive involvement of the hippocampal-amygdala complex plays a major role in explicit memory loss. Damage to associative cortical areas likely is involved in repetition priming deficits. The relative integrity of primary motor and sensory cortical areas and of the basal ganglia likely subsume, by contrast, the normal learning of visuomotor skills.

HYPOTHESIS TESTING AND FOCUSING BEHAVIOR DURING CONCEPT FORMATION BY AMNESIC KORSAKOFF PATIENTS

Abstract Patients with Korsakoffs syndrome were compared to brain-damaged and neurologically intact control subjects on visual discrimination tasks designed to evaluate hypothesis testing and focusing behavior. Results show that Korsakoffs can formulate and use hypotheses, but that their strategies are not leading to correct solution. Rather, they perseverate with one strategy even after indications of its inappropriateness. Furthermore, that this pattern of results occurs in the presence of memory aids, suggests that Korsakoffs may have impaired cognitive functioning independent of their retention deficits.

Frontal White Matter and Cingulum Diffusion Tensor Imaging Deficits in Alcoholism

BACKGROUND Alcoholism-related deficits in cognition and emotion point toward frontal and limbic dysfunction, particularly in the right hemisphere. Prefrontal and anterior cingulate cortices are involved in cognitive and emotional functions and play critical roles in the oversight of the limbic reward system. In the present study, we examined the integrity of white matter tracts that are critical to frontal and limbic connectivity. METHODS Diffusion tensor magnetic resonance imaging (DT-MRI) was used to assess functional anisotropy (FA), a measure of white matter integrity, in 15 abstinent long-term chronic alcoholic and 15 demographically equivalent control men. Voxel-based and region-based analyses of group FA differences were applied to these scans. RESULTS Alcoholic subjects had diminished frontal lobe FA in the right superior longitudinal fascicles II and III, orbitofrontal cortex white matter, and cingulum bundle, but not in corresponding left hemisphere regions. These right frontal and cingulum white matter regional FA measures provided 97% correct group discrimination. Working Memory scores positively correlated with superior longitudinal fascicle III FA measures in control subjects only. CONCLUSIONS The findings demonstrate white matter microstructure deficits in abstinent alcoholic men in several right hemisphere tracts connecting prefrontal and limbic systems. These white matter deficits may contribute to underlying dysfunction in memory, emotion, and reward response in alcoholism.

Comparisons of Korsakoff and Non-Korsakoff Alcoholics on Neuropsychological Tests of Prefrontal Brain Functioning

BACKGROUND Evidence suggests that alcoholics exhibit particular deficits in brain systems involving the prefrontal cortex, but few studies have directly compared patients with and without Korsakoffs syndrome on measures of prefrontal integrity. METHODS Neuropsychological tasks sensitive to dysfunction of frontal brain systems were administered, along with standard tests of memory, intelligence, and visuospatial abilities, to 50 healthy, abstinent, nonamnesic alcoholics, 6 patients with alcohol-induced persisting amnestic disorder (Korsakoffs syndrome), 6 brain-damaged controls with right hemisphere lesions, and 82 healthy nonalcoholic controls. RESULTS Korsakoff patients were impaired on tests of memory, fluency, cognitive flexibility, and perseveration. Non-Korsakoff alcoholics showed some frontal system deficits as well, but these were mild. Cognitive deficits in non-Korsakoff alcoholics were related to age, duration of abstinence (less than 5 years), duration of abuse (more than 20 years), and amount of alcohol intake. CONCLUSIONS Abnormalities of frontal system functioning are most apparent in alcoholics with Korsakoffs syndrome. In non-Korsakoff alcoholics, factors contributing to cognitive performance are age, duration of abstinence, duration of alcoholism, and amount of alcohol consumed.

Comparative neuropsychology and Korsakoff's syndrome. I—Spatial and visual reversal learning

Abstract Alcoholic Korsakoffs disease is associated with widespread cerebral damage. Damage to the hippocampus and its major connections has been linked directly to the severe anterograde amnesia observed in Korsakoff patients. However, since other brain regions also are destroyed with chronic alcoholism, a thorough description of any additional behavioral abnormalities is essential to understanding the alcoholic Korsakoff syndrome. Using spatial and visual reversal-learning paradigms popular in comparative and physiological psychology, we have observed profound defects in the formation of stimulus-reinforcement associations by a group of 12 Korsakoffs in comparison to 13 alcoholic and 11 aphasic control subjects. A group of 15 patients with Huntingtons disease showed severe deficits on visual but not spatial reversals, and their poor visually-based performance was qualitatively different from that of the Korsakoff patients.

Comparative neuropsychology and Korsakoff's syndrome. III--Delayed response, delayed alternation and DRL performance.

Performance of alcoholic Korsakoff patients was compared with that of patients with Huntingtons disease. Brocas aphasia or alcoholism (without clinical signs of memory impairment) on delayed alternation (DA) and delayed response (DR) tests. Korsakoffs were impaired on both tasks, and Huntington patients were impaired on DA only. In a separate experiment, performance by Korsakoffs was compared to that of alcoholic and normal controls on four DRL schedules. Korsakoffs tended to be overresponsive, making errors of commission early within a schedule, and consequently, obtaining fewer reinforcements than the controls.

Dichhaptic hand-order effects with verbal and nonverbal tactile stimulation ☆

Abstract The palms of normal right-handed subjects were stimulated dichhaptically, i.e., with competing, bimanually presented tactile stimuli consisting of pairs of letters, pairs of digits, or pairs of line orientations. The subjects were required to identify both stimuli in a particular order, and order of report was compared between hands and across stimulus materials. Results indicated right-hand superiority for letters and left-hand superiority for lines; no hand differences occurred for digits. However, observed differences between hands appeared with second reports only, suggesting that measures of tactile storage are more sensitive to laterality differences than measures closer in time to actual stimulation.