Decreased brain metabolism in neurologically intact healthy alcoholics.

OBJECTIVE: The extent to which cerebral dysfunction in alcoholics is related to the direct effects of alcohol in the brain rather than to indirect mechanisms and/or alcohol withdrawal remains unclear. The purpose of this study was to evaluate whether healthy alcoholics with no evidence of alcohol-associated complications showed changes in brain glucose metabolism. METHOD: Positron emission tomography and [18F]-fluorodeoxyglucose were used to measure regional brain metabolism. The study group consisted of 22 normal, healthy, right-handed volunteers and 22 neurologically intact, healthy, right-handed alcoholics tested 6 to 32 days after alcohol discontinuation. RESULTS: Alcoholics showed significantly lower whole brain metabolism than normal control subjects. Normalization of regional metabolic values to the whole brain metabolic rate revealed that the left parietal and right frontal cortices were the most affected regions. Although the whole brain metabolic rate was correlated with the amount of time since alcohol discontinuation, the "normalized" decreases in left parietal and right frontal glucose metabolism were not. CONCLUSIONS: These findings support the contribution of the direct effect of alcohol as well as alcohol withdrawal on the changes in regional brain metabolism seen in alcoholics. They also provide evidence of cerebral changes in neurologically intact healthy alcoholics.     

Locus of control in alcoholics: comparative study of 64 alcoholics vs 50 hospitalized patients and 50 normal controls

The locus of control is a construct that consists of factors that influence and contribute to a person's belief concerning the extent and degree to which he or others can influence life events. The study had four purposes. They were to examine differences between psychiatric inpatients alcoholics and non alcoholics on the internal, chance and powerful others subscales of the French version of Levenson's scale, to evaluate differences on these scores between the alcoholics who accepted the alcohol program treatment proposed at the admission (hospitalization of 15 days with a directive and structured context) and those who refused this treatment, to assess the impact of treatment on the Levenson scale scores of the alcoholics, and finally to determine whether the Levenson scale scores differentiate between treatment successes and failures (evaluated at three months). 171 subjects were divided into three groups: 64 patients hospitalized in psychiatry for chronic alcoholism (ICD-10 criteria for alcohol dependency), 50 patients hospitalized in psychiatry for an other pathology (control group) and 57 healthy subjects (normal group). These subjects filled out the IPC (Internal, Powerful others, Chance) scale of Levenson, different from the I-E (Internal-External) Rotter's scale because it distinguishes two types of externality: one imprevisible, the chance, and the other previsible, the powerful others. The results showed that the alcoholics as the controls are more external than the healthy subjects (Chance and Powerful others subscales). They also showed that the alcoholics who refused the alcohol treatment program proposed at the admission were more internal than those who accepted. We also found that, during the treatment, the alcoholics' scores of Internality increased while their scores of externality (Chance and Powerful others) decreased. This decreasing was also found with the check inpatients. So these changes would have connections with an "hospitalization factor" and wouldn't be due to the alcohol treatment. As for the last purpose, there were no significant differences between the initial locus of control scores of the successes and those of the failures.     

Effects of alcoholism and gender on brain metabolism

OBJECTIVE: Proton magnetic resonance spectroscopy was used to evaluate gender influences on alcohol-associated changes in brain metabolism. METHOD: Concentrations of N-acetylaspartate, choline-containing compounds, myo-inositol, and creatine plus phosphocreatine in frontal lobe gray matter and white matter were estimated in eight women and 17 men who were recently detoxified from long-term alcoholism. Twelve women and 13 men with no history of alcoholism were used as a comparison group. RESULTS: In male and female alcoholics, frontal lobe white matter concentrations of N-acetylaspartate were significantly lower (-8.8%) than those seen in nonalcoholic comparison subjects. In the frontal lobe gray matter region, a significant alcoholism status-by-gender interaction and follow-up analyses revealed that female alcoholics had significantly lower N-acetylaspartate concentrations (-10.73%) relative to female comparison subjects, while male alcoholics and male comparison subjects had similar levels of this metabolite (<1% difference). CONCLUSIONS: Lower concentrations of white matter N-acetylaspartate, which may indicate neuronal loss or dysfunction, is equally severe in men and women with comparable alcohol abuse histories. However, female alcoholics exhibited significantly less N-acetylaspartate in frontal gray matter relative to female nonalcoholic comparison subjects, which could mean that female alcoholics are more susceptible to gray matter injury than their male counterparts. However, this finding could also be explained by higher-than-expected levels of N-acetylaspartate in the healthy female comparison group.     

Development of alcohol-associated cues and cue-induced brain activation in alcoholics.

The objective of this study was to develop new standardized alcohol-associated cues and assess their effects on brain activation with functional magnetic resonance imaging (fMRI). Pictures of alcoholic and neutral beverages and affectively neutral pictures were presented to 44 abstinent alcoholics and 37 age-matched healthy control subjects. We assessed the skin conductance response, and the elicited arousal and valence. Alcoholics and control subjects did not differ in arousal, valence or skin conductance response evoked by alcohol-associated and affectively neutral stimuli, while nonalcoholic beverages were rated as more unpleasant and arousing by alcoholics compared with control subjects. In the fMRI pilot study, alcohol and abstract pictures were presented to six abstinent alcoholics and induced a significant activation of brain areas associated with visual emotional processes such as the fusiform gyrus, parts of the brain reward system (basal ganglia and orbitofrontal gyrus) and further brain regions in the frontal and parietal cortices associated with the attention network. These observations suggest that standardized pictures of alcoholic beverages can be used to assess brain circuits involved in the processing and evaluation of alcohol cues.     

Parental alcohol use and brain volumes in early- and late-onset alcoholics.

BACKGROUND: Studies have shown that alcoholics have smaller brain volumes than non-alcoholic cohorts, but an effect of family history (FH) of heavy drinking on brain volume has not been demonstrated. We examined the relationship between an FH of heavy drinking and both brain shrinkage as measured by the ratio of brain volumes to intracranial volume (ICV) as well as maximal brain growth as measured by ICV in early-onset and late-onset alcoholics. METHODS: With T1-weighted resonance imaging, we measured ICV, brain volume, and white and gray matter volume in adult treatment-seeking late-onset and early-onset alcoholics with either a positive or a negative FH of heavy alcohol use, and in healthy control subjects. We also calculated brain shrinkage using a ratio of soft tissue volumes to ICV. RESULTS: The FH positive alcoholic patients had significantly smaller ICVs than FH negative patients, suggesting smaller premorbid brain growth. Brain shrinkage did not correlate with FH. Late-onset alcoholics showed a greater difference in ICV between FH positive and FH negative patients than early-onset alcoholics. Late-onset FH positive patients also had significantly lower IQ scores than late-onset FH negative patients, and IQ scores were correlated with ICV. CONCLUSIONS: These data provide evidence that parental alcohol use might increase risk for alcoholism in offspring in part by a genetic and/or environmental effect that might be related to reduced brain growth.     

Craving for alcohol and dopamine receptor sensitivity in alcohol-dependent men and control subjects

Summary. Detoxified alcohol-dependent men and control subjects were repetitively exposed by sight and smell to either a neutral cue (tea) or an alcohol-related cue (their favourite alcoholic beverage) to provoke a maximum craving response. Additionally, their dopamine receptor sensitivity was evaluated by measuring growth hormone (HGH) response to stimulation with the dopamine receptor agonist apomorphine (APO). It was hypothesized that the subjects' desire to drink (craving) is related to their dopaminergic activity. In both groups, craving increased in the presence of the alcohol stimulus with significantly higher craving scores in alcoholics than in controls. However, in none of the groups and at no cue exposure did the craving response correlate with the individuals' dopaminergic activity as reflected by HGH release. Therefore, this study cannot add support to the hypothesis that craving for alcohol is associated with dopamine receptor sensitivity in abstinent alcoholics or healthy control subjects. Received June 16, 1999; accepted January 4, 2000     

Platelet MAO activity as a biological marker in subgroups of alcoholism

In the Stockholm Adoption Study, two types of alcoholism, "Type I" and "Type II", have been identified on the basis of genetic predisposition. In the present study, this classification has been applied to a clinical sample. The two types of alcoholism were clinically clearly identifiable. Type I alcoholism was characterized by late onset and few social complications. Type II alcoholism was characterized by early onset, use and abuse not only of alcohol, but also of glue, cannabis, amphetamine and opioids, together with several social complications. The subjects with Type II alcoholism had also more alcoholism and depression among their first-degree relatives than the subjects with Type I alcoholism. Furthermore, the two types of alcoholism were separable by means of the biological marker - platelet MAO activity. While platelet MAO activity was normal in Type I alcoholics, as compared with healthy controls, it was clearly low in the Type II alcoholics. This subclassification of alcoholism seems to be of value in future studies concerning the etiology, epidemiology and treatment of alcoholism.     

Behavioral symptoms and psychiatric diagnoses among 162 children in nonalcoholic or alcoholic families

OBJECTIVE: People with alcoholic relatives have high rates of alcohol abuse and dependence as adults, but their patterns of problems earlier in life are less clear. Many studies have not controlled for parental disorders other than alcoholism or for parents' socioeconomic status and general life functioning. The authors' goal was to conduct a study controlling for such factors. METHOD: Personal structured interviews and a behavioral checklist were administered to the parents of 162 children 7 years old or older whose fathers had participated in the 15-year follow-up of 453 sons of alcoholics with no history of antisocial personality disorder and sons of nonalcoholic comparison subjects originally selected from a university population. RESULTS: There was no significant relationship between a family history of alcoholism and childhood diagnoses of conduct, oppositional, or attention deficit disorders or with behavioral checklist summary scores. However, children with alcoholic relatives apparently have a slightly higher risk for drug abuse or dependence than those without alcoholic relatives. CONCLUSIONS: Once familial antisocial disorders and familial socioeconomic status are controlled for, a family history of alcoholism does not appear to relate to childhood externalizing disorders.     

Cerebellar and frontal cortical benzodiazepine receptors in human alcoholics and chronically alcohol-drinking rats.

Postmortem cerebellar and frontal cortical membrane homogenates from human alcoholics, control subjects without neurological or psychiatric illnesses, and rats that chronically drank alcohol were studied to determine the binding characteristics of an imidazobenzodiazepine, [3H]Ro 15-4513. This ligand binds to classical gamma-aminobutyric acidA (GABAA)/benzodiazepine receptors, as well as to a "diazepam-insensitive" site associated with the GABAA receptor complex in the cerebellar granule cell layer. There were no differences in the density of the binding sites between alcoholics and their controls, between alcohol-drinking AA rats that had a choice between 10% alcohol or water for about 10 weeks and their controls, or between Wistar rats that had been given 20% alcohol as their only fluid for 4 months and their controls, which were pair-fed isocalorically with sucrose. The affinity for the cerebellar binding of [3H]Ro 15-4513 was higher in the alcoholics than the controls. No differences were observed in the frontocortical binding. No affinity differences were observed in the rat models. There were no differences between the groups in the characteristics of [3H]Ro 15-4513 binding to human cerebellum in the presence of micromolar diazepam, thus revealing the diazepam-insensitive binding. When this component was subtracted from the total cerebellar binding, to reveal the diazepam sensitive binding, both the KD and Bmax were lower in the alcoholic than the control group. The binding of [3H]muscimol, a GABAA agonist, tended to be higher in the frontal cortices of alcoholics; a similar trend for greater effects was observed in the alcoholics for the GABA inhibition of [3H]Ro 15-4513 binding. These results suggest that no drastic changes occur through chronic alcohol abuse in the numbers of cerebellar and frontocortical benzodiazepine receptors in humans and rodent models; however, the data indicate that the alcoholics have either acquired or innate differences in classical benzodiazepine recognition sites of the cerebellum and in the coupling of these sites to GABAA sites in the frontal cortex, without any differences in cerebellar granule cell-specific diazepam-insensitive [3H]Ro 15-4513 binding sites.     

Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study

Imaging studies in patients with Type II alcohol dependence have revealed significant reductions in dopamine (DA) D2 receptor availability. Here we assessed the effects of alcohol detoxification in DA D2 receptors in alcoholic subjects. We evaluated 14 patients with Type II alcohol dependence tested within 6 weeks of detoxification and then re-tested 1–4 months later while alcohol free. The comparison group comprised 11 healthy controls. PET was used with [¹¹C]raclopride to measure DA D2 receptors. Eight alcoholics and all control subjects were tested with a CTI 931 PET scanner and six alcoholics with a Siemens HR+ PET scanner. Data were analyzed separately for the studies done in the different scanners. Comparisons between early and late alcohol detoxification showed no significant changes in DA D2 receptor availability (B_max/K_d) for the studies done with the CTI and the HR+ scanners. Comparison with controls showed lower DA D2 receptor levels in caudate and putamen in alcoholics tested during early detoxification and in caudate during late detoxification. These studies replicate previous findings of lower striatal DA D2 receptors in alcoholics than in controls and absence of significant recovery during alcohol detoxification. These findings suggest that low DA D2 receptor availability in alcoholics is not due to alcohol withdrawal and may reflect a predisposing factor.     

Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study

Imaging studies in patients with Type II alcohol dependence have revealed significant reductions in dopamine (DA) D2 receptor availability. Here we assessed the effects of alcohol detoxification in DA D2 receptors in alcoholic subjects. We evaluated 14 patients with Type II alcohol dependence tested within 6 weeks of detoxification and then re-tested 1-4 months later while alcohol free. The comparison group comprised 11 healthy controls. PET was used with [11C]raclopride to measure DA D2 receptors. Eight alcoholics and all control subjects were tested with a CTI 931 PET scanner and six alcoholics with a Siemens HR+ PET scanner. Data were analyzed separately for the studies done in the different scanners. Comparisons between early and late alcohol detoxification showed no significant changes in DA D2 receptor availability (B(max)/K(d)) for the studies done with the CTI and the HR+ scanners. Comparison with controls showed lower DA D2 receptor levels in caudate and putamen in alcoholics tested during early detoxification and in caudate during late detoxification. These studies replicate previous findings of lower striatal DA D2 receptors in alcoholics than in controls and absence of significant recovery during alcohol detoxification. These findings suggest that low DA D2 receptor availability in alcoholics is not due to alcohol withdrawal and may reflect a predisposing factor.     

Frontal lobe atrophy and central motor conduction time in chronic alcoholics.

The central motor conduction time (CMCT) was investigated in 12 cases of chronic alcoholism with frontal lobe atrophy, 12 cases of chronic alcoholism without frontal lobe atrophy, and 12 age-matched healthy controls. The CMCT was significantly prolonged in the chronic alcoholics with frontal lobe atrophy as compared to the chronic alcoholics without frontal lobe atrophy and the healthy controls. A significant positive correlation was noted between the CMCT and the degree of frontal lobe atrophy. The CMCT may be prolonged in chronic alcoholics with frontal lobe atrophy.     

Cognitive impairment and central motor conduction time in chronic alcoholics

The non-invasive technique of transcranial magnetic stimulation (TMS) was used in 62 chronic alcoholics to assess the functional status of descending motor pathways. The main aims of this study were: to investigate asymptomatic upper motor neuron dysfunction in alcoholics as well as to assess its relationship with parameters reflecting the intensity of exposure to alcohol; and to evaluate a possible relationship between central motor conduction time (CMCT) prolongation and neuropsychological measures of alcohol-related brain damage. Compared to control subjects, chronic alcoholics exhibited a significant prolongation of CMCT (23 out of 62 subjects). No significant correlation was found between CMCT prolongation and intensity and duration of abuse, presence of peripheral neuropathy, or brain atrophy on CT scans. Prolongation of CMCT from the upper limb correlated significantly with impairment of frontal skills on neuropsychological testing (p<0.01). These findings suggest that TMS may be a sensitive method for the detection in alcoholics of subtle neurological dysfunction, not confined to motor pathways.     

Phase-specific brain change of spatial working memory processing in genetic and ultra-high risk groups of schizophrenia

Spatial working memory (WM) processing has 3 distinct phases: encoding, maintenance, and retrieval and its dysfunction is a core feature in schizophrenia. We examined phase-specific brain activations associated with spatial WM in first-degree relatives of schizophrenia (genetic high risk, GHR), ultra-high risk (UHR) subjects, patients with schizophrenia, and healthy controls. We used an event-related functional magnetic resonance imaging in 17 GHR subjects, 21 UHR subjects, 15 clinically stable patients with schizophrenia and 16 healthy controls, while subjects were performing a spatial delayed-response task. During the encoding phase, the GHR group showed increased activation in the fronto-parietal regions, whereas the UHR and schizophrenia groups showed significantly less activation in these regions than did the healthy control group. Especially, frontal activation was strongest in GHR subjects, followed by healthy controls, and occurred to a lesser degree in the UHR group, with the least activation occurring in the schizophrenia group. During the maintenance phase, the thalamus showed a differential activation, similar to frontal activation pattern during the encoding phase. During the retrieval phase, no prominent differential activations were found. Increased activations were observed in the superior temporal gyrus during the encoding and maintenance phases in the GHR, UHR, and schizophrenia groups relative to healthy controls. Our findings suggest that functional deficits associated with spatial WM processing emerge in the UHR before the onset of schizophrenia and compensatory neural processes exist in the GHR with genetic liability to schizophrenia.     

Normalization of regional cerebral blood flow in alcoholics during the first 7 weeks of abstinence

Twenty-two institutionalized alcoholics were studied after 1, 3, 5 and 7 weeks of abstinence with measurements of the regional cerebral blood flow (rCBF), psychometric testing and clinical ratings. Twenty-two healthy volunteers served as age-matched controls. Mean rCBF was significantly reduced in the alcoholics at all measurements compared to the controls. The older alcoholics (median cut) showed a 9% increase of rCBF from the 1st to the 7th week (P less than 0.01). The mean rCBF in these alcoholics also increased more in the right than in the left hemisphere (P less than 0.05) during the investigation. The differences between the alcoholics and the controls were most pronounced in the right frontal lobe. The mean flow changes were correlated to improvement in clinical state. Right hemisphere and frontal lobe flow decreases were more accentuated in older alcoholics.     

Regional networks underlying interhemispheric connectivity: an EEG and DTI study in healthy ageing and amnestic mild cognitive impairment

Interhemispheric coherence derived from electroencephalogram (EEG) recordings is a measure of functional interhemispheric connectivity. Diffusion tensor imaging (DTI) determines the integrity of subcortical fiber tracts. We studied the pattern of subcortical fiber tracts underlying interhemispheric coherence and its alteration in 16 subjects with amnestic mild cognitive impairment (MCI), an at risk syndrome for Alzheimer's disease, and 20 cognitively healthy elderly control subjects using resting state EEG and high resolution DTI at 3 T. We used a multivariate network approach based on principal component analysis to determine effects of coherence on the regional pattern of diffusivity. Temporo-parietal coherence in the alpha band was significantly correlated with diffusivity in predominantly posterior white matter tracts including posterior corpus callosum, parietal, temporal and occipital lobe white matter, thalamus, midbrain, pons, and cerebellum, both in MCI subjects and controls (P < 0.05). In MCI subjects, frontal coherence in the alpha band was significantly correlated with a predominately frontal pattern of diffusivity including fiber tracts of the anterior corpus callosum, frontal lobe white matter, thalamus, pons, and cerebellum (P < 0.05). The study provides a methodology to access specific networks of subcortical fiber tracts subserving the maintenance of interhemispheric resting state coherence in the human brain.     

EEG phenotype in alcoholism: increased coherence in the depressive subtype

OBJECTIVE: Electroencephalography (EEG) power and coherence changes may be trait markers for alcoholism providing clues to brain mechanisms of vulnerability. However, it is unclear whether alpha power and coherence differences reflect reversible toxic or withdrawal effects of alcohol. METHOD: The EEGs of 10 non-abstinent and 16 long-term abstinent alcoholics (7.7 +/- 5.8 years) and 25 controls were analyzed. Levels of anxiety and depression were assessed by questionnaire. RESULTS: No statistically significant EEG power differences were observed between groups, although the numerical difference between alcoholics and controls was similar to that previously reported. Bilateral, intrahemispheric, posterior coherences were significantly increased in the alpha and beta frequency bands both in long-term abstinent and non-abstinent alcohol-dependent subjects - particularly when depressiveness was included as a covariate. CONCLUSION: These results suggest that increased EEG-coherence (cortical synchronization) may serve as endophenotype for alcoholism in conjunction with increased depressiveness and point to a possible involvement of GABAergic and/or glutamatergic neurotransmission.     

Verbal reasoning deficits in alcoholics

The Conceptual Level Analogies Test (CLAT), a well-constructed test of analogical reasoning, was given to groups of middle-aged male alcoholics and control subjects in two separate studies. As predicted, the alcoholics had lower CLAT scores than nonalcoholics in both studies. These results support the generalized-diffuse model of the neuropsychological effects of alcoholism. Contrary to prediction, alcoholics differed from control subjects as much on the easy analogies as they did on the hard analogies, which suggested that alcoholics differ both qualitatively and quantitatively from nonalcoholics in cognitive impairment. Finally, in two of three studies in our laboratory, familial alcoholics had significantly lower CLAT scores than nonfamilial alcoholics. These findings emphasize the importance of considering familial history of alcoholism when studying the neuropsychological functioning of alcoholics.     

Alcohol-associated stimuli activate the ventral striatum in abstinent alcoholics

Summary. Alcohol-associated cues may act as conditioned stimuli that activate the brain reward system and motivate alcohol intake in alcoholics. Alcohol-associated visual stimuli were presented during functional magnetic resonance imaging. An activation of the ventral putamen was observed in alcoholics but not in control subjects. Patients with a strong activation of the ventral putamen relapsed during the next three months. This observation supports the hypothesis that alcohol use affects areas involved in brain reward circuits and that their stimulus-induced activation may be associated with an increased risk for relapse. Received December 20, 2000; accepted March 21, 2001     

Functional magnetic resonance imaging study of cognitive control in the healthy relatives of schizophrenia patients.

BACKGROUND: The predisposition, or diathesis, to schizophrenia is highly heritable. The manner in which this genetic diathesis is manifest in the central nervous system is largely unknown, although healthy relatives of schizophrenia patients show executive processing deficits associated with prefrontal cortical impairments. METHODS: The current study evaluated brain activity in 21 healthy relatives of schizophrenia patients and 20 demographically similar control subjects during correct trials on a stimulus-response incompatibility task. During the first part of each trial, participants represented and maintained the instruction for that trial; during the second part, participants used the instruction either to make an automatic response or to overcome this prepotent response. RESULTS: Behaviorally, relatives were slower when overcoming the prepotent response. Analyses focused on the first part of the trial indicated that both groups showed activity in middle frontal (Brodmann areas 46 and 9) and anterior cingulate (Brodmann area 32) gyri. However, control subjects showed significantly greater activity in dorsal prefrontal cortex (Brodmann areas 9, 8, and 6) when preparing to overcome the prepotent response, whereas patients' relatives showed prefrontal activity later, when making the response. CONCLUSIONS: Using an event-related design showed distinct prefrontal brain abnormalities associated with the genetic diathesis to schizophrenia.