The value of instability: an investigation of intrasubject variability in brain activity among obese adolescent girls.

BACKGROUND: The present study investigated the value of intrasubject variability (ISV) as a metric for revealing differences in cognition and brain activation associated with an obese versus lean body mass. METHODS: Ninety-six adolescents with a lean body mass (body mass index (BMI) percentile=5-85), and 92 adolescents with an obese body mass (BMI percentile ⩾95), performed two tasks (Stroop and Go/No-Go) challenging response inhibition skills. The s.d. values and averages of their reaction time and P300 electroencephalographic responses to task stimuli were computed across trials. RESULTS: During the Go/No-Go task, the reaction times of subjects with an obese body mass were more variable than those of their lean body mass peers. Accompanying the greater ISV in reaction times was a group difference in P300 amplitude ISV in the opposite direction across both tasks. The effect sizes associated with these group differences in ISV were marginally greater than the effect sizes for the comparisons of the group means. CONCLUSIONS: ISV may be superior to the mean as a tool for differentiating groups without significant cognitive impairment. The co-occurrence of reduced ISV in P300 amplitude and elevated ISV in reaction time may indicate a constraint among obese adolescent girls in the range of information processing strategies and neural networks that can compete to optimize response output. It remains to be determined whether this decrement in neural plasticity has implications for their problem solving skills as well as their response to weight management interventions.

A family history of substance dependence obscures the group differences in brain function associated with HIV-1 and ART.

BACKGROUND: Recently, the NIH called for additional research on the topic of viral and host factors contributing to impaired cognitive and neural function in HIV/AIDS patients and their response to antiretroviral treatment. This investigation responds to that call by examining a host factor, a family history of substance dependence, often overlooked in cognitive and neuroimaging studies of HIV/AIDS. METHODS: We categorized 146 HIV-1 seropositive patients receiving antiretroviral treatment (ART) and 92 seronegative volunteers by the presence or absence of alcohol, cocaine, or heroin dependence affecting a biological parent. Seropositive patients were further categorized by the estimated ability of their individual ART regimens to penetrate the CNS. The indicator of brain function was a 3-7Hz oscillatory electroencephalographic response (theta ERO) evoked by target stimuli presented during a simple selective attention task. RESULTS: The analysis revealed that the presence of a family history of substance dependence obscured the reduction in frontal theta ERO power accompanying the presence of HIV-1 as well as the improvement in frontal theta ERO power accompanying treatment with ART agents estimated to have greater (n=41) versus lesser (n=105) CNS penetrance. Secondary analyses employing sLORETA source localization techniques revealed that the source of the theta ERO response was similarly reduced by the presence of either HIV-1 or a family history of substance dependence. CONCLUSIONS: We conclude that a family history of substance dependence complicates and obscures the subtle neurophysiological changes which typically accompany HIV/AIDS and ART. Studies of new therapeutic agents for HIV-1-associated cognitive and neurophysiological impairments must consider this complication and exclude or control it.

GABRA2 and KIBRA genotypes predict early relapse to substance use.

BACKGROUND: Numerous single nucleotide polymorphisms (SNPs) within different genes have been associated with alcohol and drug involvement or known risk factors for involvement, such as impaired cognitive control. The ability of these SNPs to predict re-involvement, defined here as abstinence failure during treatment, has not been thoroughly tested. METHODS: We studied a small sample (n=146; 49% female) of residential substance abuse treatment program patients who had maintained 2-6 months of abstinence. They were followed for 4 months thereafter for the purpose of counting days until the first abstinence violation. The analysis used logistic and Cox regression methods to evaluate the contributions of age; sex; number of intake alcohol, drug use, and depression symptoms; and either GABRA2, CHRM2, ANKK1, BDNF, or KIBRA SNP genotypes to outcome. RESULTS: GABRA2 and KIBRA genotypes, as well as the number of intake drug abuse problems and a younger age, were associated with an increased risk of relapse. Importantly, these genotypes were found to add value to relapse prediction: the χ(2) statistic evaluating their residual contribution, after age and the number of previous drug use problems were entered, was significant. CONCLUSIONS: Genetic analyses may add value to outcome prediction. Future studies should evaluate the sensitivity and specificity of GABRA2 and KIBRA genotypes for this purpose in other racial/ethnic groups and treatment settings.

Effects of alcoholism, anxiety and depression on P300 in women: a pilot study.

OBJECTIVE: The present investigation was designed for the purpose of revealing functional brain impairments associated with alcoholism, anxiety and depression. METHOD: The subjects were 56 women, with an average (SD) age of 34.8 (7.3) years. None reported a history of neurological or major medical disorders, or drug abuse. Twenty-nine of the women met DSM-IV lifetime criteria for a diagnosis of alcohol abuse or dependence. Twenty-five women reported mild or higher levels of anxiety, as indexed by a Beck Anxiety Inventory (BAI) score greater than 7. Electroencephalographic activity was recorded while subjects performed a visual ("oddball") selective attention task comprised of rare target, rare nontarget and frequent nontarget stimuli. P300 event-related potentials elicited by the rare target and rare nontarget stimuli were analyzed. RESULTS: The initial analysis was structured as a 2 (alcoholism) by 2 (anxiety) factorial. Analyses revealed no significant effects of alcoholism on P300. However, women reporting a BAI score greater than 7 exhibited significantly smaller P300 amplitudes than their nonanxious counterparts. The P300 decrement remained significant when depression level (Beck Depression Inventory [BDI-II]) and age were entered as covariates. A separate analysis was conducted in which the 56 subjects were classified by alcoholism and depression level (BDI-II score < or =13 vs >13). The analysis revealed no significant P300 differences associated with these factors. CONCLUSIONS: It is hypothesized that anxiety might play a role in mediating or amplifying the P300 decrements that have been attributed to alcoholism and depression in women. Additional and more comprehensive studies are needed to discern the validity ofthis hypothesis.

CSD/BEM localization of P300 sources in adolescents "at-risk": evidence of frontal cortex dysfunction in conduct disorder.

BACKGROUND: Longitudinal studies have demonstrated that childhood conduct disorder is a significant risk factor for a wide range of adult psychiatric disorders. The present study attempted to identify neurophysiologic differences that might underlie this risk factor. METHODS: The study examined 158 subjects, aged 14 to 20 years. Each subject was assigned to one of four groups defined by the factorial combination of the subject's gender and the relative number (-/+) of conduct problems exhibited before age 15. Event-related electroencephalographic potentials were recorded from each subject while he or she performed a memory scanning task. Each trial consisted of the brief presentation of either two or four consonant letters, a 2-sec memorization period, and a single "probe" letter. The subject was instructed to mentally compare the probe with the memory set and execute a discriminative (match vs. mismatch) key-press response. RESULTS: Analyses of P300 event-related potentials elicited by the probe stimuli revealed a significant interaction between probe stimulus membership and conduct problems: the P300 difference between trials with matching versus mismatching probes was significantly greater in the control (CP-) group than in the CP+ group. Current source density analyses, utilizing a realistic head-shape boundary element model, revealed that CP- subjects exhibited a robust activation of the left prefrontal cortex on matching versus mismatching trials. Among CP+ subjects, the degree of prefrontal cortex activation was not significant. CONCLUSIONS: The P300 results are consistent with those reported from previous studies of adolescents with conduct problems. Our study is unique in implementing current source density-boundary element method techniques for modeling P300 sources in "at-risk" adolescents. These techniques lend greater anatomical precision to the conclusion that conduct problems are associated with a specific dysfunction of the frontal brain.

Relationship of cognitive ability to the developmental course of antisocial behavior in substance-dependent patients.

1. The present study examined cognitive differences among three groups of abstinent substance-dependent patients and a control group of non-drug users. The patient groups were defined according to their DSM III-R substance dependence diagnosis(es): heroin, cocaine, or dual alcohol and cocaine dependence. 2. In the initial analysis, which compared the four subject groups on scores from the Shipley Institute of Living Scale, no significant differences were found. However, the groups did vary on the number of Antisocial Personality Disorder (ASPD) behaviors. 3. Another set of analyses was conducted to examine the relationship between ASPD and SILS scores. Analyses of the effects of ASPD (+/-) across all of the patients revealed lower SILS scores in the ASPD-positive group. Additional analyses examined the developmental course of the ASPD effect by contrasting 1) patient groups characterized by childhood Conduct Disorder (CD) combined with adult ASPD vs. 2) childhood CD which did not continue into adulthood as ASPD vs. 3) adults who did not report childhood CD but who met other ASPD behavioral criteria as adults, vs. 4) subjects who had neither childhood CD nor adult ASPD. 4. In this analysis, it was found that patients who met diagnostic criteria for childhood Conduct Disorder, but whose antisocial behaviors resolved after age 15, had equivalent SILS scores to those patients with no childhood CD or adult ASPD. A decrement in SILS scores was only found in those patients whose antisocial behaviors persisted into adulthood. 5. ASPD adults who did not report childhood CD behaviors had normal SILS scores compared to Controls.

Predicting relapse to alcohol and drug abuse via quantitative electroencephalography.

A sensitive and specific screening test that would identify the subset of substance-abusing patients at highest risk for relapse would constitute an important advance for treatment planning. This study examined the relative value of quantitative electroencephalography as a rapid, inexpensive, and noninvasive measure of relapse potential. The subjects were 107 substance-dependent patients enrolled in residential treatment programs. All were unmedicated and free of the complicating effects of major medical and neurological disorders. Structured clinical interview data and a 5-minute recording of the resting, eyes-closed electroencephalogram were obtained after patients had verifiably maintained abstinence for 1-5 months. Patients were then monitored for relapse or successful abstinence by research staff for an ensuing 6-month period. ANCOVAs of EEG power spectral density within pre-defined frequency bands revealed an enhanced amount of high frequency (19.5-39.8 Hz) beta activity among the 48 patients who later relapsed compared to both 59 patients who maintained abstinence and 22 additional subjects with no history of substance dependence. Importantly, in subsequent logistic regression analyses, fast beta power was found to be superior to severity of illness, depression level, and childhood conduct problems in predicting relapse. With fast beta power as the sole predictor, the sensitivity, specificity, and positive and negative predictive value parameters for discriminating outcomes were 0.61, 0.85, 0.75, and 0.74, respectively. Additional ANCOVAs revealed that the EEG difference between relapse-prone and abstinence-prone groups was related to the interaction of two premorbid factors, viz., childhood Conduct Disorder and paternal alcoholism. The enhancement of fast beta electroencephalographic activity in patients who will later relapse most likely originates from a premorbid and subtle dysfunction involving frontal brain regions.

CNS recovery from cocaine, cocaine and alcohol, or opioid dependence: a P300 study.

OBJECTIVES: The goal of the present study was to evaluate the relative effects of cocaine, cocaine and alcohol, or opioid dependence on P300 event-related potentials (ERPs). In addition, the effects of selected premorbid and comorbid factors were examined. METHODS: P300 ERPs were recorded from 72 residential treatment program patients, characterized by a history of either cocaine (n=25), or cocaine and alcohol (n=18), or opioid (n=29) dependence, and 14 non-drug-dependent community volunteers. The 86 subjects completed a visual continuous performance test formed by a series of 150 presentations of individual consonant letters. They were asked to press a key whenever a letter was presented twice in succession. RESULTS: Analyses of P300 ERPs obtained on target trials revealed a similar amplitude decrement in all the patient groups. Further analyses of P300 activity in the 3 drug-dependent patient groups revealed a negative correlation between P300 amplitude and the number of DSM-IIIR childhood conduct disorder criterion behaviors as well as a positive correlation between P300 amplitude and the duration of drug abstinence. CONCLUSIONS: P300 amplitude in drug-dependent patients is influenced by a complex interaction between CNS pathology that predates, and probably promotes, the onset of drug dependence and CNS pathology that resolves during the process of recovery from drug dependence.

Antisocial personality disorder and cocaine dependence: their effects on behavioral and electroencephalographic measures of time estimation.

The present study examined time estimation performance and concurrently-recorded electroencephalographic activity among 57 residential treatment program patients previously dependent on either cocaine or cocaine and alcohol. The patients were assigned to one of two subgroups based upon the presence (n=20) versus absence (n=37) of a comorbid diagnosis of Antisocial Personality Disorder (APD). Twenty-six subjects, who had no history of substance abuse and no diagnosis of APD, were also examined. All subjects performed a psychomotor task in which they were asked to press a response key exactly 2 s after the onset of a visual cue. Analyses revealed that cocaine-dependent patients with APD were often premature in their behavioral estimates of time passage. The analysis of a slow EEG potential, viz. the Contingent Negative Variation, recorded over the 2 s time estimation interval, also suggested premature response preparation in the cocaine-dependent, APD-positive group. Correlational analyses revealed that the number of conduct problems reported prior to age 15 was a better predictor of both premature responding and CNV amplitude than either severity of cocaine dependence, alcohol use, or anxious or depressed mood. The potential relevance of these findings for studies of future time orientation and delay discounting behavior are discussed.

Genetics of event-related brain potentials in response to a semantic priming paradigm in families with a history of alcoholism.

Event-related brain potentials (ERPs) are altered in patients with a variety of psychiatric disorders and may represent quantitative correlates of disease liability that are more amenable to genetic analysis than disease status itself. Results of a genomewide linkage screen are presented for amplitude of the N4 and P3 components of the ERP, measured at 19 scalp locations in response to a semantic priming task for 604 individuals in 100 pedigrees ascertained as part of the Collaborative Study on the Genetics of Alcoholism. N4 and P3 amplitudes in response to three stimuli (nonwords, primed words [i.e., antonyms], and unprimed words) all showed significant heritabilities, the highest being.54. Both N4 and P3 showed significant genetic correlations across stimulus type at a given lead and across leads within a stimulus, indicating shared genetic influences among the traits. There were also substantial genetic correlations between the N4 and P3 amplitudes for a given lead, even across stimulus type. N4 amplitudes showed suggestive evidence of linkage in several chromosomal regions, and P3 amplitudes showed significant evidence of linkage to chromosome 5 and suggestive evidence of linkage to chromosome 4.

The P300 brain potential is reduced in smokers.

RATIONALE: Tobacco smoking is the most prevalent type of substance abuse, yet its biobehavioral etiology is little understood. Identification of differences between smokers and non-smokers on basic characteristics of neurocognitive functioning may help to elucidate the mechanisms of tobacco dependence. OBJECTIVES: This study assessed the relationship between smoking status and the P300 component of event-related potential (ERP) while controlling for potential confounders such as alcoholism, drug abuse, and psychopathology. METHODS: The ERP responses elicited by a visual oddball task were measured at the mid-parietal site in 905 current smokers, 463 ex-smokers, and 979 never smokers. RESULTS: P300 amplitude was significantly lower in current cigarette smokers compared to never-smokers. Ex-smokers did not differ significantly from never-smokers. P300 reduction was also associated with alcoholism, drug dependence, and family density of alcoholism. However, after controlling for smoking, only family density of alcoholism remained a significant predictor of P300 amplitude. CONCLUSIONS: The results indicate a significant effect of smoking status on P300 amplitude which is additive to family history of alcoholism and suggest that either (1) long-term tobacco smoking may produce a reversible change in brain function, or (2) reduced P300 may be a marker of risk for nicotine dependence.

Verbal ability predicts abstinence from drugs and alcohol in a residential treatment population.

Measures of cognitive ability, depression, anxiety, antisocial personality, as well as length, type and severity of addiction were obtained from 122 substance abusers enrolled in residential treatment programs. Over a subsequent 6-mo. monitoring period, relapse to substance use was detected in 46 subjects. 17 subjects withdrew from treatment for other reasons and their relapse status was unknown. The remaining 59 maintained abstinence from alcohol or drug use throughout the monitoring period. The only variables to differentiate the groups significantly on outcome were IQ and the Verbal subtest from the Shipley Institute of Living Scale. Stepwise discriminant function analysis indicated that the Verbal component alone correctly identified 64.4% of patients who would successfully remain abstinent.

P300 decrements in teenagers with conduct problems: implications for substance abuse risk and brain development.

BACKGROUND: The purpose of this study was to evaluate the effects of conduct disorder problems, family history, gender, and age on P300 electroencephalographic potentials in teenagers. METHODS: The 257 subjects, aged 15 to 20 years, were assigned to one of twelve groups defined by the crossing of three between-subjects factors: 1) gender; 2) ranking below vs above the median number of conduct disorder problems for their gender; and 3) no family history of alcohol or drug dependence vs familial alcohol dependence vs familial heroin or cocaine dependence. RESULTS: P300 amplitude was smaller among subjects reporting a greater number of conduct problems prior to age 15 vs those reporting fewer problems of this type. No family history effects were detected. Another set of analyses examined the effects of age on conduct problem-related decrements in P300. Smaller P300 amplitudes within the posterior scalp region were associated with a greater number of conduct problems among subjects younger than 16.5 years. Among subjects greater than this median age, the effects of these behaviors were only apparent over the frontal scalp. CONCLUSIONS: It is concluded that P300 decrements previously attributed to familial alcohol/substance dependence might be the result of a coincident increase in the prevalence of conduct disorder problems. The analysis of age interactions suggests that P300 amplitude decrements observed at posterior scalp sites among subjects with more conduct problems disappear at approximately 16 to 17 years of age. After that age, decrements in frontal brain function may begin to emerge in the subset of conduct problem subjects who are at risk for developing adult antisocial personality disorder.

Heritability of event-related brain potentials in families with a history of alcoholism.

Event-related brain potentials (ERPs) are altered in patients with a variety of psychiatric disorders and may represent quantitative correlates of disease liability that are more amenable to genetic analysis than disease status itself. Estimates of heritability are presented for amplitude and latency of the N1 and P3 components of the ERP measured at 19 scalp locations in response to visual and auditory stimuli for 604 individuals in 100 pedigrees ascertained as part of the Collaborative Study on the Genetics of Alcoholism. Significant heritabilities were found for visual P3 amplitude in response to all stimuli and for visual P3 latency in response to target and novel, but not non-target, stimuli. Heritability of visual N1 latencies was uniformly low, whereas heritability of visual N1 amplitude was significant for all electrodes in response to the non-target stimuli but only for posterior electrodes in the other two stimulus conditions. Heritabilities for auditory target P3 were similar to those of the visual stimuli, with auditory target P3 amplitudes and latencies both demonstrating significant heritability. For auditory P2 in response to non-target stimuli, peak amplitude was heritable, but latency was not. Auditory N1 amplitude and latency were significantly heritable for both target and non-target conditions and did not demonstrate the anterior/posterior patterning obtained for visual N1 amplitude. This study represents the first systematic assessment of heritability of these potential neurophysiological markers in families with a history of alcoholism and suggests that many of these ERP phenotypes have heritabilities strong enough to justify genomic screening for loci jointly influencing ERP abnormalities and liability to alcoholism.

Subtypes of family history and conduct disorder: effects on P300 during the stroop test.

The goal of the present study was to identify neurophysiological differences associated with a family history of substance dependence, and its subtypes (paternal alcohol, cocaine, or opiate dependence), and with conduct disorder, and its subtypes (aggression, deceitfulness/theft, and rules violations). P300 event-related brain potentials were recorded from 210 males and females, aged 15-20 years while they performed the Stroop color-word compatibility test. Analyses revealed no significant effects of familial substance dependence on P300. However, an elevated number of conduct disorder problems was associated with a statistically significant reduction in P300 amplitude. The P300 amplitude reduction was related to the severity of the "rules violation" subtype, but was unrelated to aggression or deceitfulness and theft. It is concluded that conduct disorder can explain many of the P300 findings previously attributed to a family history of alcohol dependence. Furthermore, it appears that conduct disorder may be a heterogenous classification comprised of neurophysiologically different subtypes.

Neuropsychologic findings in cocaine-dependent outpatients.

1. Nineteen recently abstinent cocaine-dependent males were compared to 16 control subjects on a battery of neuropsychological tests. 2. The performance of cocaine-dependent subjects was inferior to the control group on tasks assessing higher level verbal skills, and on a task requiring logical sequencing of complex visual stimuli. 3. Cocaine users also performed poorly on a delayed visual memory task and on a verbal generation task, but performed better than the control group on a task assessing simple visual-motor speed. 4. Possible reasons for these findings are discussed, as are the treatment implications of these findings.

Amplitude of visual P3 event-related potential as a phenotypic marker for a predisposition to alcoholism: preliminary results from the COGA Project. Collaborative Study on the Genetics of Alcoholism.

Recent data collected at six identical electrophysiological laboratories from the large national multisite Collaborative Study on the Genetics of Alcoholism provide evidence for considering the P3 amplitude of the event-related potential as a phenotypic marker for the risk of alcoholism. The distribution of P3 amplitude to target stimuli at the Pz electrode in individuals 16 years of age and over from 163 randomly ascertained control families (n = 687) was compared with those from 219 densely affected alcoholic families (n = 1276) in which three directly interviewed first-degree relatives met both DSM-III-R and Feighner criteria at the definite level for alcohol dependence (stage II). The control sample did not exclude individuals with psychiatric illness or alcoholism to obtain incidence rates of psychiatric disorders similar to those of the general population. P3 amplitude data from control families was converted to Z-scores, and a P3 amplitude beyond 2 SD's below the mean was considered an "abnormal trait." When age- and sex-matched distributions of P3 amplitude were compared, members of densely affected stage II families were more likely to manifest low P3 amplitudes (2 SD below the mean) than members of control families, comparing affected and unaffected offspring, and all individuals; all comparisons of these distributions between groups were significant (p < 0.00001). P3 amplitude means were also significantly lower in stage II family members, compared with control family members for all comparisons, namely probands, affected and unaffected individuals (p < 0.0001), and offspring (p < 0.01). Furthermore, affected individuals from stage II families, but not control families, had significantly lower P3 amplitudes than unaffected individuals (p < 0.001). Affected males from stage II families had significantly lower P3 amplitudes than affected females (p < 0.001). Recent linkage analyses indicate that visual P3 amplitude provides a biological phenotypic marker that has genetic underpinnings.

Effects of chronic opioid dependence and HIV-1 infection on pattern shift visual evoked potentials.

The goal of the present study was to examine the effects of opioid dependence, alone and in combination with asymptomatic HIV-1 infection, on the pattern shift visual evoked potential (PSVEP). For this purpose, three groups of patients were evaluated, including patients characterized by: (1) a past history (2-4 months abstinent) of DSM-IIIR opioid dependence (i.e. in partial remission); (2) a recent history (7 days abstinent) of opioid dependence with ongoing methadone maintenance; and (3) a recent history of opioid dependence, ongoing methadone maintenance, and asymptomatic HIV-1 infection. A group of healthy, non-drug dependent volunteers was also evaluated. Analyses revealed no PSVEP differences between patients with a past history of opioid dependence and healthy volunteers. There were also no PSVEP differences between methadone-maintained patients with or without HIV-1 infection. Collectively, however, the two methadone maintenance groups exhibited significant delays in the N75 and P100 components of the PSVEP relative to the other two groups. The delay in N75 latency was strongly correlated with self-reported years of heroin abuse, but not with years of cocaine, alcohol, or other drug abuse. These results are interpreted as reflecting an adverse effect of chronic opioid dependence on neural transmission within primary visual areas of the brain.

Quantitative trait loci analysis of human event-related brain potentials: P3 voltage.

The P3 event-related brain potential (ERP) is a positive-going voltage change of scalp-recorded electroencephalographic activity that occurs between 300-500 ms after stimulus onset. It is elicited when a stimulus is perceived, memory operations are engaged, and attentional resources are allocated toward its processing. Because this ERP component reflects fundamental cognitive processing, it has found wide utility as an assessment of human mental function in basic and clinical studies. In particular, P3 attributes are heritable and have demonstrated considerable promise as a means to identify individuals at genetic risk for alcoholism. We have conducted a quantitative linkage analysis on a large sample from families with a high density of affected individuals. The analyses suggest that several regions of the human genome contain genetic loci related to the generation of the P3 component of the ERP, which are possible candidate loci underlying the functional organization of human neuroelectric activity.

Smooth pursuit eye movement dysfunction in substance-dependent patients: mediating effects of antisocial personality disorder.

Smooth pursuit eye movements were evaluated in 21 healthy volunteers and 126 patients meeting criteria for one of the following DSM-III-R dependence diagnoses: alcohol (n = 10), cocaine (n = 44), heroin (n = 34), or dual alcohol and cocaine (n = 38). A significant reduction in tracking accuracy was found in the heroin and the dually dependent groups relative to controls. Interestingly, the eye movement dysfunction in the drug-dependent groups was no longer detectable when the effects of antisocial personality disorder were statistically removed. The magnitude of the dysfunction also correlated with several antisocial personality-related features, including an increased number of criminal charges and months of incarceration, increased problems associated with drug abuse, and lower intellectual functioning. The relationship demonstrated presently between antisocial personality disorder and eye movement dysfunction may have implications beyond studies of substance dependence.