Linkage scan of nicotine dependence in the University of California, San Francisco (UCSF) Family Alcoholism Study.

BACKGROUND: Nicotine dependence has been shown to represent a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder though only a limited number of the findings have been replicated. METHOD: In the present study, a genome-wide linkage scan for nicotine dependence was conducted in a community sample of 950 probands and 1204 relatives recruited through the University of California, San Francisco (UCSF) Family Alcoholism Study. A modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) with additional questions that probe nicotine use was used to derive DSM-IV nicotine dependence diagnoses. RESULTS: A locus on chromosome 2q31.1 at 184 centiMorgans nearest to marker D2S2188 yielded a logarithm (base 10) of odds (LOD) score of 3.54 (point-wise empirical p=0.000012). Additional peaks of interest were identified on chromosomes 2q13, 4p15.33-31, 11q25 and 12p11.23-21. Follow-up analyses were conducted examining the contributions of individual nicotine dependence symptoms to the chromosome 2q31.1 linkage peak as well as examining the relationship of this chromosomal region to alcohol dependence. CONCLUSIONS: The present report suggests that chromosome 2q31.1 confers risk to the development of nicotine dependence and that this region influences a broad range of nicotine dependence symptoms rather than a specific facet of the disorder. Further, the results show that this region is not linked to alcohol dependence in this population, and thus may influence nicotine dependence specifically.

Single nucleotide polymorphisms in the REG-CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample.

Impulsivity is a multi-faceted construct that, while characterized by a set of correlated dimensions, is centered around a core definition that involves acting suddenly in an unplanned manner without consideration for the consequences of such behavior. Several psychiatric disorders include impulsivity as a criterion, and thus it has been suggested that it may link a number of different behavioral disorders, including substance abuse. Native Americans (NA) experience some of the highest rates of substance abuse of all the US ethnic groups. The described analyses used data from a low-coverage whole genome sequence scan to conduct a genome-wide association study (GWAS) of an impulsivity phenotype in an American Indian community sample (n = 658). Demographic and clinical information were obtained using a semi-structured interview. Impulsivity was assessed using a scale derived from the Maudsley personality inventory that combines both novelty seeking and lack of planning items. The impulsivity score was tested for association with each variant adjusted for demographic variables, and corrected for ancestry and kinship, using emmax. Simulations were conducted to calculate empirical P-values. Genome-wide significant findings were observed for a variant 50-kb upstream from catenin cadherin-associated protein, alpha 2 (CTNNA2), a neuronal-specific catenin, in the REG gene cluster. A meta-analysis of GWAS had previously identified common variants in CTNNA2 as being associated with excitement seeking. A second locus upstream of nei endonuclease VIII-like 3 (NEIL3) on chromosome 4 also achieved genome-wide significance. The association between sequence variants in these regions suggests their potential roles in the genetic regulation of this phenotype in this population.

Two roads to rapid eye movement latency.

Although considerable attention has been paid to the accumulated body of data on sleep-related "markers" of affective illness, there has been ongoing controversy with respect to the application of these sleep measures. This report attempts to reexamine the data on the electroencephalographic sleep features of individuals with depressive illness from a different theoretical perspective. Our focus on rapid eye movement latency is intended to provide both a new interpretation of the available data and directions for future research.

Social zeitgebers and biological rhythms. A unified approach to understanding the etiology of depression.

Results of biological and psychosocial studies of depression completed in the last decade have stimulated the need for new hypotheses that synthesize these findings in a unified etiologic theory. The importance of disruption of biological rhythms on the one hand, and psychosocial losses on the other, in the causation of depressive episodes suggest one possible unifying hypothesis. The concept of loss of "social zeitgebers," ie, persons, social demands, or tasks that set the biological clock, may provide the link between biological and psychosocial theories of etiology. We suggest that a disruption of social rhythms, which may result in instability in biological rhythms, could be responsible for triggering the onset of a major depressive episode in vulnerable individuals.

Antagonism of neuropeptide YY1 receptors does not inhibit ethanol's effects on cortical EEG and ERPs in Wistar rats.

OBJECTIVE: Ethanol and neuropeptide Y (NPY) can have additive neurobehavioral effects. In the present study, the NPY Y1 receptor antagonist BIBP3226 was administered alone or in combination with a moderate dose of ethanol to determine whether it interacted with the neurobehavioral effects of ethanol. METHOD: Male Wistar rats were implanted with cortical recording electrodes and a lateral ventricular cannula. The effects of 1 nmol BIBP3226, 0.75 g/kg ethanol and the combination (BIBP3226 + EtOH) on neurophysiological activity and locomotion were then assessed. RESULTS: Ethanol significantly increased 1-2 Hz parietal cortical power and this effect was partially antagonized by BIBP3226. Peak frequencies in the parietal cortical 6-8 Hz and 8-16 Hz bands were also altered by ethanol, but these effects were not reversed by BIBP3226. BIBP3226 or ethanol, when administered alone, did not alter motor activity or cortical event-related potentials (ERPs) but administration of BIBP3226 + EtOH reduced motor activity, reduced parietal cortical N1 ERP amplitude and increased frontal cortical N1 ERP latency. CONCLUSIONS: In the present study, the most prominent effect of antagonizing central NPY Y1 receptors was a facilitation of the effects of ethanol. In particular, the effects of combined administration of BIBP3226 and ethanol are indicative of enhanced sedation and possibly cognitive impairment.

EEG fast frequency activity in the sons of alcoholics.

The EEGs of young (21-25-year-old) sons of alcoholics and their matched controls (n = 24 pairs) were computer evaluated to assess activity in the 12-20 Hz (beta) range. Subjects were blindly exposed to ethanol and placebo drinks while EEG was gathered at baseline and 90 min postconsumption. Men with alcoholic fathers [family history positive (FHP)] displayed significantly more beta activity at 90 min postethanol consumption than the men who had no alcoholic relatives [family history negative (FHN)]. In addition, when subjects were sorted into "low" and "moderate" drinkers depending on their drinking practices, additional differences were found between groups. Within the FHN subjects, moderate drinkers were found to have significantly more energy in the beta frequencies at both baseline and at 90 min postdrug than low drinkers. However, though family history positive subjects had overall increases in 12-20 Hz activity compared with the FHN subjects, no significant differences were found between moderate and low drinkers within the FHP population. Taken together, these studies suggest that drinking practices and a familial history for alcoholism can modify the beta content of the EEG in the 12-20 Hz range in young men.

Gender differences in electrophysiological responses to facial stimuli.

BACKGROUND: A facial discrimination task was adapted to be used in an event-related potential (ERP) paradigm in order to evaluate whether young women's brain responses to affective stimuli differed from those of young men. METHODS: The stimuli used to generate a late positive component of the ERP, designated the "P450," were male and female faces with neutral, sad, or happy facial expressions. Subjects were instructed to respond to the happy and sad faces but not to the neutral faces. The amplitude and latency of the P450 component was evaluated with respect to the gender of the subject, as well as the gender and emotional affect of the facial stimuli themselves. RESULTS: In all subjects, the sad faces elicited longer latency and higher amplitude P450 components as compared to the happy faces. Female subjects were found to generate significantly longer latency and higher amplitude P450 components than male subjects to both happy and sad faces. All subjects were found to respond more quickly to: male happy faces > female happy faces > female sad faces > male sad faces. CONCLUSIONS: These data suggest that the morphology of the late positive component of the ERP differs depending on the emotional expression of the stimuli, the gender of the facial stimulus, and the gender of the subject.

EEG sleep in young depressives: first and second night effects.

The sleep electroencephalogram (EEG) of young, drug-free, recurrently depressed outpatients was analyzed for 2 nights and was compared to age-matched controls using a variety of standard and computerized measures of sleep activity. On the first night, young depressives showed significantly greater difficulty in falling asleep and decreased sleep efficiency. Sleep architecture differences between the young depressives and controls were highlighted by increased percentages of Stage 2 sleep and major decreases in Stages 3 and 4 (delta wave) sleep among the depressives, as indicated by either period analyses or spectral analysis. The greatest differences in delta wave activity during night 1 were found in the first two (non-rapid eye movement (NREM) periods as measured by period analysis (NREM period 1, p less than 0.04; NREM period 2, p less than 0.001--average delta wave count) or by spectral analysis for the first 100 min of sleep (0.5-2.0 Hz). In contrast to the NREM sleep findings, various REM variables, including REM latency did not significantly distinguish the two subject groups for either night 1 or 2. Stepwise discriminant analysis demonstrated that night 1 sleep latency and delta wave counts during the second NREM period correctly classified 100% of all 16 individuals studied. The only differences between the young depressed patients and controls that remained on night 2 were significant reductions in slow-wave sleep as quantified by the computerized methods. Taken together, these findings suggest that the EEG response of young outpatients to the first night's stay in a sleep laboratory may be a useful tool for the diagnosis of depression in this age group. In addition, the use of computerized methods in this study point to an underlying deficit in delta sleep waveforms as being a prominent feature of the sleep of young depressed subjects.

Electrophysiological findings during the menstrual cycle in women with and without late luteal phase dysphoric disorder: relationship to risk for alcoholism?

This study evaluated electrophysiological (EEG, ERGs), and cognitive (neuropsychological testing) responses in patients with late luteal phase dysphoric disorder (LLPDD, DSM-III-R) and controls over the menstrual cycle. In both groups, the frequency and stability of electroencephalogram (EEG) alpha activity significantly differed over the menstrual cycle. The latency of the P3 components of the auditory event-related potentials (ERPs) did not vary as a function of the menstrual cycle, but the P3 latency was found to be later in LLPDD subjects as a group. When the LLPDD subjects were assessed based on family history of alcoholism, it was found that those with alcoholic relatives had more high-frequency alpha (9-12 Hz) in their EEG, lower P3 component amplitudes, and longer P3 component latencies when compared to LLPDD subjects without alcoholic relatives or controls. These data suggest that LLPDD may have persistent neurophysiological correlates, some of which are also in common with risk for alcoholism.

Estimation of the time course of slow-wave sleep over the night in depressed patients: effects of clomipramine and clinical response.

The distribution of slow-wave activity during sleep has been analyzed using a method related to the two-process model of sleep regulation. This method is applied to the analyses of data collected from 21 inpatients with unipolar depression who received the antidepressant clomipramine (CMI) in a pulse-loading protocol. CMI infusion was found to redistribute slow-wave activity, producing more concentration in the early part of the night, and also significantly reduced the fluctuation in slow-wave power as a function of time. These measures also distinguished clinical responders from the nonresponders. Drug responders had a significant redistribution of slow-wave activity to the earlier part of the night as compared to nonresponders. This suggests that measures of the distribution of slow-wave activity over the night may represent a good measure of clinical response to antidepressant therapy and have implications for the interpretation of the two-process model and sleep in depression.

Effects of alcohol on the EEG in Asian men with genetic variations of ALDH2.

Approximately 50% of Asians experience a facial flush following alcohol ingestion. These individuals have an inactive form of mitochondrial aldehyde dehydrogenase (ALDH) encoded by the ALDH2*2 allele. This study matched 15 flushing and 15 nonflushing Asian men on demographics and drinking histories. The 30 subjects were genotyped for ALDH2 and were evaluated both before and following placebo and 0.75 ml/kg alcohol. The two groups did not differ significantly on blood alcohol concentrations after drinking, but did differ in electroencephalographic (EEG) response on the falling phase of the blood alcohol curve. Nonflushing subjects displayed significant increases in slow-alpha EEG activity (7.5-9.0 Hz) at 90 and 150 min post-alcohol consumption, compared to flushing subjects who did not show characteristic increases in this frequency band at these timepoints. These data suggest flushers, those with at least one ALDH2*2 allele, have less of slow-alpha wave EEG response to alcohol than nonflushers with ALDH2*1/2*1 genotype.

EEG asymmetry: relationship to mood and risk for alcoholism in Mission Indian youth.

BACKGROUND: Left frontal electroencephalogram (EEG) alpha dominance has been hypothesized to be related to depressed mood as well as aversive motivation and emotion. However, few studies have prospectively evaluated electroencephalogram asymmetry during development in high-risk adolescents and children. METHODS: EEG alpha asymmetry was investigated in 134 Mission Indian children who were between 7 and 13 years of age. The relationships between electroencephalogram alpha asymmetry and age, gender, parental history of alcohol dependence, Native American heritage, and mood/ approach behaviors were explored. RESULTS: No significant relationship was found between frontal alpha asymmetry and age, gender, or behavioral measures of depressed mood and/or approach behaviors. However, participants with > or = 50% Native American heritage were significantly more likely to have greater electroencephalogram alpha power in the left frontal cortex than in the right. CONCLUSIONS: The present findings suggest that the hypothesized relationship between EEG alpha asymmetry and measures of depressed mood, aversive motivation, and emotion may not be universal in all age or ethnic groups. Additionally, though the relationship between greater degrees of Native American heritage and alpha asymmetry are not as yet clear, we suggest it may be more related to substance abuse than depression in this population of Mission Indians.

EEG sleep profiles and recurrent depression.

Earlier investigations have suggested that electroencephalographic (EEG) sleep may be altered as a function of the duration of an episode of depression. We compared the EEG sleep profiles in a group of recurrent depressives who had been depressed for less than 6 weeks with their sleep profiles as measured during their previous episode of depression. Findings in this sample of 32 patients point to the presence of specific rapid eye movement (REM) sleep abnormalities as being more pronounced earlier in the course of a depressive episode. Changes in REM latency and REM activity were also reflected in reductions in EEG spectral power in almost all bandwidths during the first REM period of the recurrent episode. These results are not easily explainable on the basis of traditional measures of clinical severity or the number of episodes.

Persistent effects of antidepressants: EEG sleep studies in depressed patients during maintenance treatment.

Electroencephalographic (EEG) sleep studies represent a research tool that can be used to examine depressed patients over different phases of their illness. We examined the long-term effects of imipramine on EEG sleep in 27 subjects who completed 3 years of maintenance treatment on imipramine without experiencing a recurrence. The analyses were performed on EEG sleep data collected prior to acute treatment, after 3 months in maintenance, and every 3 months thereafter. The major aim was to examine specific changes in rapid eye movement (REM) and slow-wave sleep (SWS) as they unfolded over the course of illness and recovery during long-term drug maintenance. The acute changes in the sleep profile produced by antidepressants remained essentially the same throughout the entire period of drug administration. The REM sleep parameters, which were affected immediately, remained essentially unchanged thereafter, even as long as 3 years into maintenance treatment. A rapid redistribution of slow-wave sleep in the first part of the night was also observed without an increase in the total amount of slow-wave sleep throughout the night. The application of spectral analysis confirmed that the sleep changes following drug administration remained stable throughout all phases of drug treatment. Thus, it appears that sustained clinical improvement is accompanied by persistent sleep alterations on tricyclic antidepressant medication.

Effects of gender and social isolation on electroencephalogram and neuroendocrine parameters in rats.

Social separation/isolation from either maternal or peer influence can induce a biobehavioral response in rodents and nonhuman primates seeming to mimic certain aspects of human psychopathology. To further explore this paradigm, the effects of 6 weeks of social isolation on electroencephalographic (EEG) recordings and hypothalamic-pituitary-adrenal (HPA) functioning were studied in male and female adult rats. Gender differences were observed in EEG and HPA axis functioning in these rats. Female rats, overall, were found to have higher levels of EEG slow-wave activity over the entire recording period, suggesting more intense levels of slow-wave sleep in those animals. Female rats were also observed to have overall higher plasma corticosterone concentrations and a lower anterior pituitary corticotropin-releasing factor (CRF) receptor density compared with male rats. The male rats, however, showed greater changes in response to social isolation than female rats. EEG power was increased as a result of social isolation in the male animals during the first 30-100 min of the recording. Reductions in the number of CRF receptors were also observed in the brains of the socially isolated rats in several cortical areas; however, again this effect was more prominent in the male animals. These studies suggest that gender is an important variable in determining the biobehavioral response to social isolation.

Electroencephalographic responses to alcohol challenge in Native American Mission Indians.

BACKGROUND: Native Americans have some of the highest rates of alcohol abuse and dependence, yet potential central nervous system risk factors responsible for the problem drinking seen in some tribes remain relatively unknown. METHODS: Background electroencephalographic (EEG) variants and response to alcohol were investigated in 48 Native American Mission Indian men between 18 and 25 years old. RESULTS: Subjects with 50% or greater Native American heritage had a significantly higher proportion of low-voltage EEG variants. Within this sample of Mission Indian men, however, a family history of alcohol dependence was associated with a greater incidence of high voltage alpha EEGs. Mission Indian men also evidenced a "less depressant, more stimulating" response to alcohol as quantified by less alcohol-induced reductions in alpha, greater EEG stability, and increased alcohol-induced beta activity. CONCLUSIONS: These findings demonstrate that certain genetically regulated EEG variants that have been previously associated with risk for alcoholism in Caucasians may also be more common in these Mission Indian men. Additionally, EEG measures of response to alcohol do not provide support for the commonly held idea that Indians are more sensitive to the depressant effects of alcohol.

The firewater myth and response to alcohol in Mission Indians.

OBJECTIVE: This study aimed to assess empirically the intensity of reaction to alcohol in a group of Native Americans. METHOD: Forty healthy, nonalcoholic Mission Indian men between the ages of 18 and 25 years were tested before and after ingestion of placebo and 0.75 ml/kg of alcohol. Subjective (self-report of feelings) and objective (blood pressure, pulse rate, and plasma cortisol level) measures of intoxication were taken before ingestion of alcohol and placebo and at 15, 30, 60, 90, and 120 minutes after ingestion. Overall effects of alcohol were evaluated, and the responses of subjects with less than 50% Native American heritage (N = 19) were compared with the responses of subjects with at least 50% Native American heritage (N = 21). RESULTS: Alcohol did not produce any significant effects on any of the objective measures of intoxication; however, the subjects reported significant subjective effects of alcohol. Subjects with at least 50% Native American heritage reported less intense effects of alcohol than did those with less than 50% Native American heritage, despite equivalent blood alcohol concentrations. CONCLUSIONS: These results contradict the "firewater myth"--the theory that Native Americans are more sensitive to the effects of alcohol. Rather, the data indicate that Mission Indian men generally may be less sensitive to alcohol's effects, a physiological characteristic that has been shown to be associated with a greater risk for alcoholism in Caucasian populations. In addition, individuals with a greater percentage of Native American heritage may be less sensitive to the subjective effects of alcohol than individuals with a smaller percentage of Native American heritage.

Evaluation of EEG alpha activity in sons of alcoholics.

The results of computer-analyzed electroencephalographic (EEG) data from 24 sons of alcoholics (family history positive [FHP]) and their matched controls (family history negative [FHN]) were compared before and 90 minutes following alcohol and placebo challenge. Blind analysis of the data revealed that FHP men had more energy in the fast-frequency alpha range (9 to 12 Hz) of their EEG than did FHN subjects at baseline. EEG response to ethanol was also found to differ between the two groups. FHN but not FHP subjects evidenced a decrease in fast-frequency alpha energy following ethanol challenge. These data support other evidence of a less intense reaction to ethanol in FHPs as measured by subjective response, body sway, and hormone levels. In addition, these findings suggest that certain normal alpha wave variants may be more common in sons of alcoholics.

Nonlinear analysis of EEG sleep states.

Recent advances in the field of nonlinear dynamics have provided new conceptual models as well as novel analytical techniques applicable to neuropsychopharmacologic studies. One measurement technique that has been recently developed in an attempt to characterize nonlinear systems in physics and biology is the estimation of dimension. Dimension may be seen as a measure of the information required to describe the current behavior of a system. We have applied these techniques to the analysis of the sleep EEG, and have found that the dimension of rapid eye movement (REM) sleep is significantly higher than non-rapid-eye-movement (NREM) sleep. These data support a preliminary hypothesis that EEG dimension may represent the number of nonlinear modes activated in the brain. Thus, sleep states of low arousal or low input would be envisioned as having low dimension (e.g., slow-wave sleep) whereas increased arousal (REM) would activate more nonlinear modes. Although more investigations will be needed to explore this hypothesis, these studies suggest that further development of nonlinear approaches to the analysis of brain systems are likely to generate new clinical measures as well as new ways of viewing brain electrical function.

Electrophysiological actions of neuropeptide Y and its analogs: new measures for anxiolytic therapy?

Neuropeptide Y (NPY) has neuromodulatory actions on multiple brain functions including endocrine, behavioral, and circadian processes. Behavioral studies suggest that NPY is a potent anxiolytic; however, little is known about how NPY affects general arousal and/or attention states. The present study evaluated the effects of NPY on spontaneous brain activity as well as auditory processing by using electrophysiological measures. Electroencephalographic (EEG) and event-related potentials (ERPs) were obtained in awake animals after intracerebroventricular administration of NPY (1.0, 3.0 nmol) and two of its analogs, active at Y1 (1.0, 3.0 nmol) and Y2 (1.0, 3.0 nmol) receptor sites. NPY was found to produce dose-related effects on electrophysiological measures. Spectral analyses of the EEG revealed that NPY produced slowing of delta activity (1-2 Hz) in the frontal cortex and high frequency theta activities (6-8 Hz) concomitant with a speeding up of low frequency theta (4-6 Hz) in cortex, hippocampus, and amygdala. At higher doses (3.0 nmols) in addition to shifts in frequency, EEG power was also significantly reduced in all frequencies (0.5-50 Hz) in cortex, and in the higher frequencies (8-32 Hz) in the amygdala. The Y1 and Y2 agonists had a somewhat different profile of EEG effects than the parent compound. At the 1 nmol dose both agonists were found to produce selective depressions in power in the hippocampus. The 3.0 nmols dose of the Y1 agonist produced decreases in EEG stability, an effect commonly produced by anxiolytic drugs, whereas the Y2 agonist produced increases in EEG stability in cortex and amygdala. Auditory processing, as assessed by ERPs, was affected most significantly in the frontal cortex where dose-dependent decreases in the N1 component of the ERP, a finding also commonly seen after anxiolytics, was found. Y1 and Y2 agonists were also found to significantly reduce the amplitude of the N1 component of the ERP but less so than the parent compound. The electrophysiological and behavioral profiles of NPY and the Y1 agonist resembles those of anxiolytics such as ethanol and benzodiazepines. Taken together these data suggest that electrophysiological measures of the actions of this peptide system may represent a new potentially useful assay for the development of anxiolytic drugs.