The relationship between folate and docosahexaenoic acid in men.

OBJECTIVE: Docosahexaenoic acid (DHA, 22:6n-3), an essential omega 3 fatty acid, may protect against disorders of emotional regulation as well as cardiovascular disease. Animal studies demonstrate that dietary folate can increase tissue concentrations of DHA, although the literature, to date, includes no human studies examining the possibility that folate status may affect plasma DHA concentrations. The objective of this study is to determine if the blood concentrations of folate and DHA are correlated in humans. DESIGN: Retrospective study. SETTING: An American research hospital. SUBJECTS: A total of 15 normal and 22 hostile and aggressive subjects, with a mean age of 38 years. METHODS: Concentrations of plasma polyunsaturated essential fatty acids and red blood cell folate (RBC folate) were obtained prior to 1996, before American flour was enriched with folate. RESULTS: RBC folate was significantly correlated with plasma DHA, r=0.57, P=0.005 in the aggressive group. Age, smoking and alcohol consumption did not alter the results. No other essential fatty acids were significantly associated with RBC folate in either group. CONCLUSIONS: The positive relationship between plasma DHA and RBC folate concentrations suggests that these two nutrients should be examined together in order to make the most accurate inferences about their relative contributions to disease pathogenesis. Our findings present one explanation why some conditions associated with hostility and low DHA status, such as cardiovascular disease and emotional disorders, are also associated with low folate status. SPONSORSHIP: National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism.

Negative association of neuroticism with brain volume ratio in healthy humans.

BACKGROUND: Brain volume decreases with normal aging. We sought to determine whether, in addition to age, individual differences in stress reactivity (i.e., neuroticism) would also predict reductions in brain volume. METHODS: Brain volume ratios were calculated for a sample of 86 healthy volunteers, based on segmented brain volumes taken from T(1)-weighted magnetic resonance imaging and corrected for intracranial volume. Standardized self-reported measures of dispositional neuroticism were concurrently obtained by administering the Revised NEO Personality Inventory. RESULTS: After statistically controlling for age and sex, neuroticism showed a significant negative association with the ratio of brain to the remainder of the intracranial volume, but was not related to intracranial volume itself. In particular, subfactors of neuroticism related to the chronic experience of arousing negative emotions were associated with reduced brain ratio. CONCLUSIONS: These results suggest that individual differences in stress reactivity contribute to reductions in brain volume observed during adulthood.

Serotonin, testosterone and alcohol in the etiology of domestic violence.

In a previous study we administered the panicogenic agent sodium lactate to a select group of perpetrators of domestic violence and comparison groups. Results of that study showed that perpetrators exhibited exaggerated lactate-induced fear, panic and rage. In this current study, we compared the cerebral spinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and testosterone obtained from perpetrators of domestic violence and a group of healthy comparison subjects. All subjects were assessed for DSM-III-R diagnoses. Perpetrators with alcohol dependence (DV-ALC) (n=13), perpetrators without alcohol dependence (DV-NALC) (n=10) and healthy comparison subjects (HCS) (n=20) were clinically assessed using the Spielberger Trait Anxiety, Brown-Goodwin Aggression Scale, Buss Durkee Hostility Inventory and Straus Conflict Tactics. Following an overnight fast and bed rest, subjects received a lumbar puncture to obtain CSF concentrations of 5-HIAA and testosterone. Perpetrators scored significantly higher on measures of aggression than HCS. DV-NALC had significantly lower concentrations of CSF 5-HIAA and higher Straus Conflict Tactics (CT) physical violence scores than DV-ALC and HCS. DV-ALC had significantly higher concentrations of CSF testosterone than DV-NALC. DV-ALC also had significantly higher Straus CT physical violence scores than HCS. DV-NALC and DV-ALC differed on 5-HIAA concentrations, testosterone concentrations, Straus CT physical violence scores and alcohol dependence. These results suggest that DV-NALC and DV-ALC groups could have different biological mechanisms mediating domestic violence.

Neuroimaging in alcoholism: ethanol and brain damage.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoaf, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) mu-Opiate receptor availability in alcoholism: First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.

Lactate-induced rage and panic in a select group of subjects who perpetrate acts of domestic violence.

BACKGROUND: Perpetrators of domestic violence frequently report symptoms of autonomic arousal and a sense of fear and/or loss of control at the time of the violence. Since many of these symptoms are also associated with panic attacks, we hypothesized that perpetrators of domestic violence and patients with panic attacks may share similar exaggerated fear-related behaviors. To test this hypothesis, we employed the panicogenic agent sodium lactate to examine the response of perpetrators to anxiety fear induced by a chemical agent. METHODS: Using a double-blind, placebo-controlled design, we infused 0.5 mol/L sodium lactate or placebo over 20 min on separate days to a select group of subjects who perpetrate acts of domestic violence and two nonviolent comparison groups. We compared their behavioral, neuroendocrine, and physiologic responses. RESULTS: Lactate administration elicited intense emotional responses in the perpetrators of domestic violence. Perpetrators evidenced more lactate-induced rage and panic and showed greater changes in speech, breathing, and motor activity than did nonviolent control subjects. There were no significant differences between the groups for any neuroendocrine or physiologic measure. CONCLUSIONS: These results are consistent with our hypothesis that some perpetrators of domestic violence have exaggerated fear-related behavioral responses.

Hippocampal volume in patients with alcohol dependence.

BACKGROUND: Smaller hippocampal volumes have been reported in the brains of alcoholic patients than in those of healthy subjects, although it is unclear if the hippocampus is disproportionally smaller than the brain as a whole. There is evidence that alcoholic women are more susceptible than alcoholic men to liver and cardiac damage from alcohol. It is not known whether the hippocampi of the female brain are more vulnerable to alcohol. METHODS: We compared the hippocampal volumes in 52 hospitalized alcoholic men and women with those of 36 healthy nonalcoholic men and women. All subjects were between 27 and 53 years of age. The hippocampal volumes were measured from sagittal T-weighted high-resolution magnetic resonance images. RESULTS: The alcoholic women had less lifetime drinking and a later age at onset of heavy drinking than alcoholic men. Both alcoholic men and women had significantly smaller right hippocampi and larger cerebrospinal fluid volumes than healthy subjects of the same sex. Only among women were the left hippocampus and the nonhippocampal brain volume also significantly smaller. The proportion of hippocampal volume relative to the rest of the brain volume was the same in alcoholic patients and healthy subjects, in both men and women. The right hippocampus was larger than the left among all subjects. Women demonstrated larger hippocampal volumes relative to total brain volume than men. Psychiatric comorbidity, including posttraumatic stress disorder, did not affect hippocampal volume. CONCLUSIONS: In chronic alcoholism, the reduction of hippocampal volume is proportional to the reduction of the brain volume. Alcohol consumption should be accounted for in studies of hippocampal damage.

Statistical analysis of functional MRI data in the wavelet domain.

The use of the wavelet transform is explored for the detection of differences between brain functional magnetic resonance images (fMRI's) acquired under two different experimental conditions. The method benefits from the fact that a smooth and spatially localized signal can be represented by a small set of localized wavelet coefficients, while the power of white noise is uniformly spread throughout the wavelet space. Hence, a statistical procedure is developed that uses the imposed decomposition orthogonality to locate wavelet-space partitions with large signal-to-noise ratio (SNR), and subsequently restricts the testing for significant wavelet coefficients to these partitions. This results in a higher SNR and a smaller number of statistical tests, yielding a lower detection threshold compared to spatial-domain testing and, thus, a higher detection sensitivity without increasing type I errors. The multiresolution approach of the wavelet method is particularly suited to applications where the signal bandwidth and/or the characteristics of an imaging modality cannot be well specified. The proposed method was applied to compare two different fMRI acquisition modalities. Differences of the respective useful signal bandwidths could be clearly demonstrated; the estimated signal, due to the smoothness of the wavelet representation, yielded more compact regions of neuroactivity than standard spatial-domain testing.

Fluoxetine normalizes increased cardiac vagal tone in bulimia nervosa.

Patients with bulimia nervosa have been reported to respond to treatment with the serotonin uptake inhibitor fluoxetine. In a preliminary study, which had a small sample size, women with bulimia nervosa were reported to have elevated cardiac vagal tone. We investigated cardiac vagal tone in women with bulimia nervosa before and after treatment with fluoxetine. At baseline, resting cardiac vagal tone, deduced from the respiratory component of heart rate variability, was quantified in 41 healthy volunteer women and in 25 women with bulimia nervosa. The bulimic women received in a parallel-group design, double blind, either placebo or fluoxetine 60 mg/24 hr for 8 weeks. All patients participated in behavioral therapy. Resting cardiac vagal tone was measured again at the end of the treatment. Women with bulimia nervosa had higher cardiac vagal tone than age-matched healthy volunteer women. Placebo had no effect on cardiac vagal tone. Fluoxetine reduced cardiac vagal tone among the women with bulimia nervosa to a level similar to the healthy volunteer women. Women with bulimia nervosa have elevated resting cardiac vagal tone. Fluoxetine normalized the elevated resting cardiac vagal tone among the women with bulimia nervosa. At both the central and peripheral levels, vagal neurons are endowed with serotonin-3 receptors. In vitro, fluoxetine desensitizes or blocks serotonin-3 receptors. A controlled trial of serotonin-3 receptor blockers is warranted in bulimia nervosa.

Behavioral and neuroendocrine responses to m-chlorophenylpiperazine in subtypes of alcoholics and in healthy comparison subjects.

OBJECTIVE: The purpose of this study was to explore central serotonergic functions in subgroups of alcoholics and in healthy comparison subjects. METHOD: The mixed serotonin (5-HT) agonist/antagonist m-chlorophenylpiperazine (m-CPP) was administered to male alcoholic patients who were classified according to the criteria of von Knorring et al. as type I alcoholics (late onset) (N = 16) or type II alcoholics (early onset with antisocial traits) (N = 24) and to 22 healthy comparison subjects. Psychological, physiological, and neuroendocrine measures were obtained before and after the m-CPP infusion. RESULTS: m-CPP elicited subtype-related differential effects among the alcoholics; the type I alcoholics reported more anger and anxiety, and the type II alcoholics reported increased euphoria and a greater likelihood of drinking. The healthy comparison subjects exhibited a greater increase in plasma ACTH response to the m-CPP infusion than the alcoholics regardless of subtype. CONCLUSIONS: Differences in certain 5-HT receptor functions may explain some of the clinical characteristics that differentiate the type II and type I subgroups of alcoholic patients. Furthermore, alcoholics may have reduced sensitivity of 5-HT2C receptors in comparison with healthy subjects.

Fluctuations in schizophrenic births by year.

BACKGROUND: It has previously been reported that births of individuals who later develop schizophrenia vary by birth year. METHOD: Birth data were analysed on 34,024 individuals diagnosed with DSM-III-R disorganised, catatonic, and undifferentiated schizophrenia using time series analysis. RESULTS: Minor yearly fluctuations were observed but did not achieve statistical significance. Thus earlier findings reported in the literature could not be replicated using a different statistical approach. CONCLUSION: The findings do not support theories which assume major yearly fluctuations in the births of individuals with schizophrenia. Such theories include the perinatal effects of influenza, temperature variation, and the effects of severe weather.

Statistical methods in the Fourier domain to enhance and classify images.

A mathematical model, for which rigorous methods of statistical inference are available, is described and techniques for image enhancement and linear discriminant analysis of groups are developed. Since the gray values of neighboring pixels in tomographically produced medical images are spatially correlated, the calculations are carried out in the Fourier domain to insure statistical independence of the variables. Furthermore, to increase the power of statistical tests the known spatial covariance was used to specify constraints in the spectral domain. These methods were compared to statistical procedures carried out in the spatial domain. Positron emission tomography (PET) images of alcoholics with organic brain disorders were compared by these techniques to age-matched normal volunteers. Although these techniques are employed to analyze group characteristics of functional images, they provide a comprehensive set of mathematical and statistical procedures in the spectral domain that can also be applied to images of other modalities, such as computed tomography (CT) or magnetic resonance imaging (MRI).

Birth seasonality in bipolar disorder, schizophrenia, schizoaffective disorder and stillbirths.

BACKGROUND: More than 40 studies have been done on seasonal birth patterns for schizophrenia, but only two small studies have been done for DSM-III-R bipolar disorder and none for schizoaffective disorder. Two studies have also reported a significant relationship between schizophrenia births and stillbirths. METHODS: In the largest study to date, birth data from four states was obtained on 126,987 state psychiatric hospitals inpatients divided into 'process' schizophrenia (disorganized, catatonic, undifferentiated), paranoid schizophrenia, schizoaffective disorder, bipolar disorder and major depression. Time series analysis compared these births to all general births and to stillbirths. RESULTS: 'Process' schizophrenia, paranoid schizophrenia, schizoaffective disorder and bipolar disorder all had statistically significant seasonal excess births from December through March (p = 0.0000). The largest excess was 5.8% for bipolar disorder. Major depression had significant excess births from March through May. Time series analysis showed statistically significant coherences between major depression and bipolar disorder (0.995) and between schizoaffective disorder and both 'process' schizophrenia (0.977) and bipolar disorder (0.977). Unexpectedly, a significant coherence was also found between paranoid schizophrenia and bipolar disorder (0.972). Excess stillbirths were found for each month from January through June and a significant coherence was found between stillbirths and paranoid schizophrenia (0.998). CONCLUSIONS: This study demonstrates that DSM-III-R bipolar disorder and schizoaffective disorder both have an excess of winter births, similar to that found in schizophrenia. Time series analysis, however, suggests that the causes may not be identical. Major depression, by contrast, has an excess of spring births.

Monitoring the source of memory in detoxified alcoholics.

The ability to monitor the source of remembered information and related reflective cognitive processes was examined in normal volunteers and detoxified alcoholics. Normal volunteers were very accurate judges of whether remembered events were presented as stimuli or were self-generated, even when memory was tested 2 days later. In contrast, a subgroup of otherwise cognitively unimpaired alcoholics demonstrated impairments in the ability to track the source of remembered knowledge and were also less able to inhibit intrusion errors in recalling information from memory. These findings provide preliminary evidence of an impairment in cognitive control functions in certain alcoholics. This conclusion is supported by associated findings indicating that, among alcoholics, performance on explicit memory tasks that required reflective cognitive operations were positively correlated with glucose utilization rates in left prefrontal, temporal, and posterior orbital frontal cortical regions.

Behavioral and endocrine responses to clomipramine in panic disorder patients with or without alcoholism.

Central nervous system serotonin functions may differ between certain subgroups of alcoholics, patients with panic disorder, and healthy volunteers. To investigate these possibilities we administered the serotonin uptake inhibitor, clomipramine (12.5 mg, i.v.), to patients with alcohol dependence, patients with panic disorder with or without alcohol dependence, and healthy volunteers. Alcoholics did not differ from healthy volunteers in their neuroendocrine or behavioral responses. In contrast, patients with panic disorder exhibited marked dysphoric reactions and/or panic attacks following low-dose i.v. clomipramine, whereas their neuroendocrine responses were similar to the other two groups. Patients with panic disorder may have super-sensitive postsynaptic serotonin receptors in areas of their central nervous system, which are important for mood regulation.

Neuropsychological functioning in detoxified alcoholics between 18 and 35 years of age.

OBJECTIVE: The authors determined 1) cognitive functioning in detoxified alcoholics who had alcohol-related problems for a relatively brief time and 2) relationships between neuropsychological test scores and recent and chronic alcohol consumption patterns, childhood symptoms of hyperactivity/minimal brain dysfunction, and extent of familial alcoholism. METHOD: The subjects were 101 detoxified, drug-free alcoholics between 18 and 35 years of age who had consumed excessive amounts of alcohol (average of 114 g four to five times per week) for an average of 6 years. An average of 39 days after the last drink each alcoholic was given an extensive battery of neuropsychological tests assessing language skills, attention, motor skills, intelligence, memory, and cognitive functioning related to the frontal regions of the brain. RESULTS: Only four individuals evidenced mild cognitive dysfunction. Current psychiatric condition, anxiety and depressive states, and liver dysfunction were not related to cognition. Relationships of cognition of lifetime estimates of alcohol consumption (average of 189 kg) and number of days from last drink to testing were determined to be nonlinear and suggested that greater lifetime consumption predicted worse performance and that longer abstinence predicted better performance. Neither extent of familial alcoholism nor number of childhood signs and symptoms of hyperactivity/minimal brain dysfunction was predictive of cognition except that more antisocial behavior predicted poorer cognitive functioning. CONCLUSIONS: Cognition in young alcoholics, averaging 6 years of excessive alcohol consumption, was within normal limits, even though greater lifetime consumption predicted lower test scores and longer abstinence predicted higher scores.

Decreased cingulate and precuneate glucose utilization in alcoholic Korsakoff's syndrome.

Localized cerebral glucose utilization was determined for nine abstinent alcoholic men with Korsakoff's syndrome and 10 age-matched normal men who underwent positron emission tomography with [18F]2-fluoro-2-deoxyglucose (FDG). Patients with Korsakoff's syndrome showed relatively decreased glucose utilization in cingulate and precuneate areas. These decreases persisted even after correction for group differences in ventricular and sulcal cerebrospinal fluid measured on computed tomography. Electroencephalographic recordings at the time of FDG uptake showed no group differences, a finding that demonstrates that the metabolic differences could not be explained by differences in physiological arousal at the time of scanning. It is concluded that the decreased glucose utilization in the patients reflects a disruption of memory circuitry, the Papez circuit, caused by diencephalic lesions induced by thiamine deficiency.

Prenatal origin of schizophrenia in a subgroup of discordant monozygotic twins.

Neuropathological, obstetrical, and epidemiological evidence increasingly suggest that some cases of adult-onset schizophrenia have prenatal or neonatal etiological roots. We evaluated the developmental histories of 23 monozygotic twin pairs discordant for schizophrenia to determine when they markedly and permanently began diverging from each other in motor skills or unusual behavior. Seven of the twins (30%) who later developed schizophrenia had become permanently different from their cotwins by age 5 years. The early divergence group differed from the others by multivariate tests (p = 0.002) for within-twin pair effects and by univariate tests for physical anomaly scores (p = 0.01), total finger ridge counts (p = 0.001), family history of psychosis (p = 0.004), and serious perinatal complications or low birth weight (p = 0.05). It is concluded that some cases of adult-onset schizophrenia are associated with prenatal events, which may include neurodevelopmental abnormalities or specific insults such as anoxia or infectious agents.

Pharmacologic maintenance of abstinence in patients with alcoholism: no efficacy of 5-hydroxytryptophan or levodopa.

Pharmacologic enhancement of central nervous system serotonin and dopamine functions has been postulated to improve maintenance of abstinence in patients with alcoholism. To test this hypothesis, patients with alcoholism who completed a 42-day inpatient treatment program were randomized to be administered, in a double-blind fashion, either 5-hydroxytryptophan and carbidopa, levodopa and carbidopa, or placebo for 1 year. Eight of 31 patients who entered the analysis remained abstinent from alcohol for 1 year; however, there was no significant effect of the treatment condition on maintenance of abstinence. Baseline psychologic measures showed that patients who abstained from alcohol had more education and higher scores on memory function tests. Measures of cerebrospinal fluid obtained before the start of the study indicated that all patients who had higher concentrations of the dopamine metabolite homovanillic acid relapsed, suggesting that further research is needed to elucidate the role of dopamine in alcoholism.

Ethanol dependence and withdrawal selectively alter localized cerebral glucose utilization.

The 2-deoxyglucose technique was used to determine local cerebral glucose utilization (LCGU) in over 50 brain regions of rats physically dependent upon ethanol and compared to those of acutely intoxicated and those undergoing an overt ethanol-withdrawal syndrome. Dependent-intoxicated rats (average blood ethanol concentration 64 mM) had decreased LCGU in 13/54 regions, including those associated with the limbic system, cerebellum, and motor system. The ethanol withdrawal syndrome was associated with 17/50 gray regions showing an increase, including regions involved with motor function, auditory system, and mammillary bodies-anterior thalamus-cingulate cortex pathway. The most pronounced differences between these groups occurred in regions associated with motor function, cerebellar function, anterior thalamus, and median raphe. Comparisons between dependent-intoxicated and acutely intoxicated rats (average blood ethanol concentration 66 mM) revealed that acute intoxication was associated with a relatively greater reduction in LCGU in regions involved with sensory-related functions, mammillary bodies, and median raphe. With the development of dependence, adaptation occurred in these regions except for inferior colliculus and median raphe. Dependence was also associated with a relative decrease in LCGU in white matter, limbic system, and extrapyramidal motor system.

Regional cerebral glucose utilization in chronic organic mental disorders associated with alcoholism.

Localized cerebral utilization rates for glucose (CMRglu) were determined in 10 detoxified patients with alcoholic organic mental disorders and in 7 age-equivalent normal volunteers using [18F]2-fluoro-2-deoxyglucose positron emission tomography. Although gray and white matter CMRglu were not significantly different, normalized CMRglu was increased in the left cerebellar and parietal cortical regions and decreased in the right posterior white matter and anterior temporal regions of alcoholic patients, and the pattern of regional CMRglu differed between the two groups. The results suggest functional disruption of right-sided and frontal brain regions and hyperactivity of cerebellar-cortical connections in alcoholic chronic organic mental disorders.