Structural brain deficits in schizophrenia. Identification by computed tomographic scan density measurements.

Research has suggested the presence of brain damage as a cause or concomitant of chronic schizophrenia. The most recent research in this area has been the identification of abnormalities in schizophrenia by computed tomographic (CT) scans. A study was done to investigate localized changes in CT scan density numbers in the brains of schizophrenic patients, as opposed to the brains in normal control subjects. Twenty-four normal subjects and 23 schizophrenic patients were tested with CT scans. Density measurements in each area of the brain (left, right, anterior and posterior) were compared to three separate CT scan levels. Of six measurements of anterior left-hemisphere density, it was found that five showed lower density in schizophrenic brains, as compared with normal brains. Of the remaining 18 measurements that evaluated other areas of the brain, only three differentiated between schizophrenic patients and normal subjects. The results support the hypothesis that there are primary structural deficits in some schizophrenic patients, and these deficits are centered in and around the anterior area of the left (dominant) hemisphere. The results also demonstrated further implications.

Genetic vulnerability to drug abuse. The D2 dopamine receptor Taq I B1 restriction fragment length polymorphism appears more frequently in polysubstance abusers.

Alcoholics are more likely than nonalcoholics to display the Taq I A1 restriction fragment length polymorphism of the D2 dopamine receptor gene, according to four of six studies that examined alcoholics and controls. The current study examines whether the association observed in alcoholism might extend to other addictive substances by examining D2 dopamine receptor Taq I A and B restriction fragment length polymorphisms in polysubstance users and controls free of significant substance use. We hypothesized a stronger association for the B1 restriction fragment length polymorphism since it lies closer to dopamine receptor protein coding and 5' regulatory regions. Heavy polysubstance users and subjects with DSM-III-R psychoactive substance use diagnoses displayed significantly higher Taq I B1 frequencies than control subjects; Taq I A1 results for these comparisons were less robust. These results are consistent with a role for a D2 dopamine receptor gene variant marked by these restriction fragment length polymorphisms in enhanced substance abuse vulnerability.

Hemispheric asymmetries in schizophrenia.

The growing literature on hemispheric asymmetries in schizophrenic populations is critically reviewed. Studies of lateral asymmetries in schizophrenics are discussed which have employed a wide range of methodologies, including assessment of motor, sensory, electrophysiological, neuropsychological, and structural abnormalities. This literature is discussed in relation to two theoretical viewpoints, one emphasizing impaired functioning of the corpus callosum, and the other positing left hemisphere overactivation and dysfunction in schizophrenic populations. It is concluded that the hypothesis of impaired callosal function has not been adequately tested because of methodological problems, the most serious of which is the failure to show differential deficit. The hypothesis of left hemisphere abnormality has gained consistent support, although methodological problems were noted. This research suggests a structural locus for schizophrenic pathology which is consistent with the symptomatology of the disorder, and provides avenues for further research.

Intravenous cocaine decreases cardiac vagal tone, vagal index (derived in lorenz space), and heart period complexity (approximate entropy) in cocaine abusers.

We assessed the effects of i.v. cocaine on parasympathetic and sympathetic nervous system activity, and on the complexity vs. regularity of changes in heart rate over time. Fourteen otherwise healthy men with histories of i.v. cocaine abuse received bolus injections of cocaine (20 mg or 40 mg) and placebo (saline) on different days. Cardiovascular measures derived from the electrocardiogram, including heart rate, Porges' vagal tone (respiratory sinus arrhythmia), the 0.10 Hz rhythm, Toichi's vagal index, Toichi's sympathetic index, and approximate entropy (ApEn), were measured continuously. As predicted, cocaine produced tachycardia, accompanied by pronounced decreases in response to 40 mg cocaine in two different vagal tone indexes that precisely mirrored the increases in heart rate. The measure of sympathetic (and vagal) neural influences on the heart (0.10 Hz wave) also decreased in response to cocaine. Converging evidence from Toichi's vagal index supported the conclusion that the tachycardia from cocaine was due to withdrawal of cardiac vagal tone. These findings, and evidence that cocaine decreased cardiovascular complexity, contradict the prevailing assumption that the mechanism by which cocaine produces tachycardia is sympathetic (beta-adrenergic). We discuss implications for cardiac arrhythmias associated with cocaine abuse and death due to overdose.

Alcohol challenge with sons of alcoholics: a critical review and analysis.

Studies are reviewed in which response to acute administration of alcohol was compared between individuals with and without family histories of alcoholism (FH+, FH-). This research represents a search for a psychobiological marker for alcoholism. A methodological critique of the procedures reported in this literature is then presented. Finally, a conceptual model is suggested in which differences in the response to alcohol between FH+ individuals and FH- individuals must be understood in relation to time after drinking alcohol. This Newtonian differentiator model proposes that sons of alcoholics exhibit acute sensitization as blood alcohol level rises and acute tolerance as blood alcohol level falls, compared with sons of nonalcoholics. Therefore, FH+ subjects find alcohol more rewarding because they accentuate the pleasurable, excitatory aspects of initial intoxication and attenuate the feelings of anxiety and depression that predominate as blood alcohol levels drop.

A behavior-genetic approach to multiple chemical sensitivity.

This report emphasizes the application of behavior-genetic designs to the study of sensitivity to toxic chemicals, and features of multiple chemical sensitivity and substance abuse that are polar opposites. The implications of these issues for future research are discussed in relation to twin, adoption, and sibling pair studies, as well as in relation to the degree to which genetically selected lines of rodents that have been developed in the alcoholism field are applicable to multiple chemical sensitivity.

Testing the neural sensitization and kindling hypothesis for illness from low levels of environmental chemicals.

Sensitization in the neuroscience and pharmacology literatures is defined as progressive increase in the size of a response over repeated presentations of a stimulus. Types of sensitization include stimulant drug-induced time-dependent sensitization (TDS), an animal model related to substance abuse, and limbic kindling, an animal model for temporal lobe epilepsy. Neural sensitization (primarily nonconvulsive or subconvulsive) to the adverse properties of substances has been hypothesized to underlie the initiation and subsequent elicitation of heightened sensitivity to low levels of environmental chemicals. A corollary of the sensitization model is that individuals with illness from low-level chemicals are among the more sensitizable members of the population. The Working Group on Sensitization and Kindling identified two primary goals for a research approach to this problem: to perform controlled experiments to determine whether or not sensitization to low-level chemical exposures occurs in multiple chemical sensitivity (MCS) patients; and to use animal preparations for kindling and TDS as nonhomologous models for the initiation and elicitation of MCS.

Conditioned compensatory response to alcohol placebo in humans.

An autonomic response opposite in direction to the effect of alcohol (i.e., a conditioned compensatory response) was found in normal social drinkers given alcohol placebo. Seven males received placebo in a distinctive drinking room after receiving vodka and tonic in two sessions in the same room; seven more males received distilled water in three sessions in that room. The response to placebo, consisting of decreased pulse transit time and finger skin temperature, was antagonistic to alcohol. The results support the application of the classical conditioning model of alcoholism to humans.

The skin-flushing response: autonomic, self-report, and conditioned responses to repeated administrations of alcohol in Asian men.

This study examined the skin-flushing response in Asian men, which is a low-risk factor for alcoholism. Asian men who did and did not flush to alcohol consumed 0.5 g/kg ethanol during three sessions with alcohol, and placebo in a fourth session. The results indicated that: (a) Asian men who flushed to alcohol showed pronounced cardiovascular changes that did not exhibit differential tolerance over 3 sessions, (b) there were surprisingly few self-reported mood differences in response to alcohol between those who did and did not flush, and (c) finger-pulse amplitude decreased and self-ratings of "boastful" increased significantly in response to placebo challenge in those men who did not flush. These results raise questions about the psychological mechanisms by which the skin-flushing response inhibits the development and expression of alcoholism.

Effect of cocaine on vagal tone: a common factors approach.

This paper discusses a distinct cardiovascular pattern that is common to a wide variety of abused substances. The pattern consists of tachycardia that appears mediated by withdrawal of vagal inhibition, as indicated by decreases in cardiac vagal tone. This decrease in vagal tone was particularly robust with i.v. cocaine given to experienced cocaine abusers in a residential research setting. Following 40 mg i.v. cocaine, heart rate increased by approximately 30 beats/min at the same time that vagal tone decreased by approximately 2 log units. The theoretical significance of these findings is based on evidence that the results reflect a common factor among many abused drugs, but not the few aversive drugs that have been studied in this paradigm.

A twin study on sensation seeking, risk taking behavior and marijuana use.

The contribution of genetic and environmental factors to the covariation between risk-taking and marijuana use was assessed in adolescent twins. Genetic factors were found to significantly influence some traits (i.e. risk-taking attitude), while familial environmental factors were important for others (i.e. sexual promiscuity). For marijuana use, genetic and environmental factors were equally important; however, the association between risk taking and marijuana use may not be comparable for different behaviors. Results suggest that different etiological factors may underlie various risk taking traits which is relevant to both prevention efforts and attempts to identify genes involved in risk taking and shared genetic influences with substance use.

Family history influence on drug abuse severity and treatment outcome.

Influence of parental alcohol/substance abuse on methadone maintenance therapy (MMT) outcome was examined in 164 DSM-III-R opioid dependent adults with no other current DSM Axis I disorder. Family history positive patients had more DSM-III-R opioid dependence symptoms and were more likely to be classified as severely dependent. However, when placed on identical daily doses of methadone (50 mg), they had lower rates of illicit opioid use but higher rates of cocaine use than family history negative patients. Both effects remained significant after adjusting for gender and race. These results suggest that common genetic factors may underlie both susceptibility to heroin dependence and response to therapeutic methadone treatment.

Hemisphericity, expressivity and autonomic arousal.

An exploratory study was performed concerning autonomic-central nervous system relationships in humans. Four groups of subjects were selected on the basis of two variables reflecting styles of central activity, hemisphericity (as measured by lateral eye movements) and facial expressivity. These groups were exposed to two stressor tasks. A marginally significant relationship was found between right hemisphericity and facial expressivity. Right hemisphericity subjects had higher heart rates. Highly expressive subjects and left hemisphericity subjects each tended to show larger autonomic responses to stress, and subjects in whom both characteristics were combined showed particularly heightened responsiveness. It was concluded that individual differences in central nervous system activation are related to autonomic arousal.

Efficacy of pattern feedback for the dissociation of heart rate and respiration rate.

The present study assessed the efficacy of pattern feedback for producing integrative and dissociative patterns of heart rate (HR) and respiration rate (RR). 60 uninformed subjects were assigned to six groups in which beat-by-beat feedback was contingent upon production of a specific pattern of increased ( ), decreased ( ), or unchanged (=) HR and RR during 11 feedback trials. Concomitant changes in respiratory volume and general activity (GA) were also recorded. Groups given feedback for HR and RR changes in the same directions (HR RR and HR RR ) ANd for changes in opposite directions (HR RR and HR RR ) were generally unable to produce the respective patterns, indicating that pattern feedback does not enable subjects to produce a wide range of HR-RR patterns. However, evidence of dissociation of HR and RR was obtained in the HR RR= and HR RR= groups in which HR changed significantly in the appropriate directions without significant changes in RR. These results are not consistent with the view that RR changes are necessary for HR control, although significant concomitant changes in respiratory volume and GA indicated that HR control was non-specific relative to these variables.

Cardiovascular responses of individuals with type A behavior pattern and parental coronary heart disease.

Cardiovascular and other responses of stress of subjects considered to be at risk for coronary heart disease (CHD) were studied in order to evaluate two hypothesized pathways in the link between CHD risk factors and the disease process. Forty-seven male subjects with and without a parental history of CHD and with either the Type A or Type B behavior pattern were exposed to two psychological stressors (reaction time and Stroop Color-World test) and one physical stressor (isometric hand grip). Subjects with a parental history of CHD showed larger finger pulse amplitude responses to the two psychosocial stressors, and Type A subjects had larger diastolic blood pressure responses to all three stressors. These results indicated that subjects at greater risk for CHD had more substantial peripheral vascular responses to the stressors compared to low risk subjects; there were no differences in sympathetic cardiac responses related to contractility. The results are discussed in terms of potential mediating mechanisms in the development of CHD.

Cardiovascular responses to naloxone challenge in opiate-dependent individuals.

Vagally mediated tachycardia appears to be a common response to abused drugs and, therefore, has implications for abuse liability. To test the specificity of this common factor, we determined whether the tachycardia to naloxone in opiate-dependent individuals has a significant vagal component. Naloxone challenge (0.4 mg, IM) in 19 opiate-dependent men and women was associated with highly reliable tachycardia, but no significant change in vagal tone index, a noninvasive measure of parasympathetic inhibitory control of the heart. We conclude that tachycardia during naloxone-precipitated withdrawal is not vagally mediated. Thus, there is some degree of specificity to the common factor of vagally mediated tachycardia to abused drugs because it was ruled out in at least one drug (naloxone) with aversive subjective effects.

Human conditioned compensatory response to alcohol cues: initial evidence.

Alcohol cues elicited a conditioned autonomic response that was opposite in direction to the effect of alcohol. Normal male social drinkers given placebo following four alcohol conditioning sessions showed a compensatory response consisting of decreased pulse transit time, vasomotor activity, and finger temperature. This pilot research, supports the application of a classical conditioning model to human alcohol problems.

Offspring of alcoholics have enhanced antagonistic placebo response.

In this study, 85 college-age men who reported normal drinking practices believed they were drinking malt liquor when they actually drank dealcoholized beer. Following drinking, 11 subjects with an alcoholic biological father showed a significantly larger heart rate decrease (p less than .05) than subjects with a nonalcoholic father. The results are discussed in terms of opponent process and classical conditioning theories of addiction, and the etiological pathway from risk factor to final manifestation of alcoholism.

Prior exposures to the laboratory enhance the effect of alcohol.

We compared responses to 0.6 g/kg alcohol of normal male drinkers in a laboratory environment that was new to the subjects with the responses of a second group in the same environment who had two prior exposures to the laboratory environment and procedures. Alcohol-induced increases in heart rate, cheek temperature and self-reported intoxication were greater in the subjects who had previous exposure to the laboratory environment than in the subjects who had no such previous exposure. Differences in blood alcohol concentration (BAC) also were found between the two environments. However, differences in the physiological and self-report measures were found after matching subjects in terms of BAC. These results suggest that novelty effects may contaminate alcohol responses in novel laboratory environments, and they add to our understanding of nonpharmacological factors in the responses to drugs.

Chronic tolerance and sensitization to alcohol in sons of alcoholics: II. Replication and reanalysis.

Data from D. B. Newlin and J. B. Thomson (1991) were reanalyzed, and data from an independent replication study were analyzed, relative to tonic (baseline) and phasic (response to alcohol challenge) aspects of drinking alcohol administered at the same dose on several occasions. Among the high-risk men (sons of alcoholic fathers), linear trends across days for resting (predrinking) baselines were opposite to alcohol-evoked changes for finger pulse amplitude, finger temperature, and skin conductance in Study 1 and for pulse transit time and body sway (static ataxia) in Study 2. In contrast, the structure of the low-risk men's (sons of nonalcoholic parents) data was precisely the opposite. Results are discussed in terms of sensitization as a potential mechanism that relates vulnerability to final manifestation of addictive behavior.