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Objective: Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of al...

Emotion regulation and the manner in which it is comprised play a key role in the motivation for drugs and alcohol. As such, the bio-behavioral processes underpinning aspects of emotion regulation behavior may provide expedient targets for treatment development. This review will examine some of the robust emotional, psychophysiological, and neurobiological adaptations that sub-serve affect regulation behaviors during early abstinence from addiction and assess their potential as targets for treatment development. During early abstinence from addiction, individuals report problems with emotional awareness and impulse control during distress as well as enhanced, persistent negative mood in the face of acute psychological stress. In line with this, psychophysiological research studies have used non-affective indices of emotional awareness to show poor interoceptive accuracy. Moreover, imaging research has highlighted hypofunctional prefrontal circuitry in regulatory brain regions and amygdala/insula adaptations that are also compatible with decrements in emotional awareness, enhanced provoked dysphoria and decreased impulse control. There is also some evidence to suggest that targeting these indices of emotion regulation behavior using mindfulness-based meditation and medication therapies may be effective in improving outcome. The biological construct of emotion regulation has helped to provide an important heuristic framework within which to develop novel treatment markers. However, there remains a need for more contextual and situational-based research to achieve a more holistic understanding of emotion regulation for improved clinical application.

The Aberdeen birth cohorts of 1921 and 1936 (ABC21 and ABC36) were subjected to IQ tests in 1932 or 1947 when they were aged about 11y. They were recruited between 1997–2001 among cognitively healthy community residents and comprehensively phenotyped in a long-term study of brain aging and health up to 2017. Here, we report associations between baseline cognitive test scores and long-term cognitive outcomes. On recruitment, significant sex differences within and between the ABC21 and ABC36 cohorts supported advantages in verbal ability and learning among the ABC36 women that were not significant in ABC21. Comorbid physical disorders were self-reported in both ABC21 and ABC36 but did not contribute to differences in terms of performance in cognitive tests. When used alone without other criteria, cognitive tests scores which fell below the −1.5 SD criterion for tests of progressive matrices, namely verbal learning, digit symbol and block design, did not support the concept that Mild Cognitive Impairment (MCI) is a stable class of acquired loss of function with significant links to the later emergence of a clinical dementia syndrome. This is consistent with many previous reports. Furthermore, because childhood IQ-type data were available, we showed that a lower cognitive performance at about 64 or 78 y than that predicted by IQ at 11 ± 0.5 y did not improve the prediction of progress to MCI or greater cognitive loss. We used binary logistic regression to explore how MCI might contribute to the prediction of later progress to a clinical dementia syndrome. In a fully adjusted model using ABC21 data, we found that non-amnestic MCI, along with factors such as female sex and depressive symptoms, contributed to the prediction of later dementia. A comparable model using ABC36 data did not do so. We propose that (1) MCI criteria restricted to cognitive test scores do not improve the temporal stability of MCI classifications; (2) pathways towards dementia may differ according to age at dementia onset and (3) the concept of MCI may require measures (not captured here) that underly self-reported subjective age-related cognitive decline.

Background:Peripheral immune system cytokines may play an integral role in the underlying sensitized stress response and alcohol craving during early alcohol withdrawal. To date, the nature of these immune changes during early abstinence have not been examined.Methods:A total of 39 early abstinent, treatment-seeking, alcohol-dependent individuals and 46 socially drinking controls were exposed to three guided imageries: stress, alcohol cue and neutral. These were presented randomly across consecutive days. Plasma measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-10 (IL-10), were collected at baseline, immediately after imagery and at various recovery time-points. Ratings of alcohol craving, negative mood and anxiety were also obtained at the same time-points.Results:The alcohol group demonstrated decreased basal IL-10 compared with controls particularly following exposure to alcohol cue. They also showed a dampened TNFα and TNFR1 response to stress and cue, respectively, and a generalized suppression of IL-6. In the alcohol group, these immune system adaptations occurred alongside significant elevations in anxiety, negative mood and alcohol craving.Conclusions:Findings demonstrate that broad immunosuppression is still observed in alcohol-dependent individuals after 3 weeks of abstinence and may be linked to motivation for alcohol.

Stress is a pivotal motivator for drinking, drug use, and relapse. Over the last decade, we have developed a human paradigm that allows us to model stress-induced craving and elucidate some of the biobehavioral adaptations associated with craving inside the laboratory and relapse outside of the laboratory. Findings from this body of research have corroborated clinical and preclinical data in showing that during protracted abstinence, drug wanting may be a dysphoric state marked by tonic stress system sensitivity, phasic stress system dysregulation, and an inability to cognitively and emotionally regulate in the face of challenge. As there is an urgent need for new food and drug administration (FDA) approved medications, we suggest that attenuation of the negative craving f0025state and enhancement of prefrontal executive processes may provide novel targets for medications development. We present data from a series of studies showing that the alpha-2 adrenergic agonist, guanfacine, may attenuate drug use via these biobehavioral mechanisms.

Aims Chronic drug abuse leads to sex-specific changes in drug cue and stress physiologic and neuroendocrine reactivity as well as in neural responses to stress and cue-related challenges and in executive function such as inhibitory control, cognitive flexibility and self control. Importantly, these functions have been associated with high risk of relapse and treatment. Alpha-2 agonism may enhance inhibitory cognitive processes in the face of stress with sex-specific effects, however this has not been previously assessed in cocaine dependence. Method Forty inpatient treatment-seeking cocaine dependent individuals (13F/27 M) were randomly assigned to receive either placebo or up to 3mgs of Guanfacine. Three laboratory sessions were conducted following 3–4 weeks of abstinence, where patients were exposed to three 10-min personalized guided imagery conditions (stress, drug cue, combined stress/cue), one per day, on consecutive days in a random, counterbalanced order. The Stroop task was administered at baseline and immediately following imagery exposure. Results Guanfacine treated women improved their performance on the Stroop task following exposure to all 3 imagery conditions compared with placebo women (p = 0.02). This improvement in cognitive inhibitory performance was not observed in the men. Conclusions Enhancing the ability to cognitively regulate in the face of stress, drug cues and combined stress and drug cue reactivity may be key targets for medications development in cocaine dependent women.

Objective As sex differences in substance dependence may impinge upon the perception and regulation of emotion, we assess emotional intelligence (EI) as a function of gender, menstrual cycle (MC) phase and hormonal changes in early abstinent cocaine-dependent individuals who abuse alcohol (CDA). Methods Study 1: The Mayer, Salovey, and Caruso Emotional Intelligence Test (MSCEIT) was administered to 98 CDA (55 M/43 F) and 56 healthy (28 M/28 F) individuals. Performance in women was also assessed by MC phase. Study 2: The MSCEIT was administered to 28 CDA (19 M/9 F) who received exogenous progesterone (400 mg/day) versus placebo for 7 days (study 2). Results Study 1: Healthy females were better than healthy males at facilitating thought and managing emotions. This gender discrepancy was not observed in the CDA group. Additionally, all women in the high compared with the low progesterone phase of their MC were better at managing their emotions. Study 2: Exogenous progesterone improved ability to facilitate thought in both males and females. Conclusions CDA women may be vulnerable to difficulties managing and regulating emotions. Gonadal hormones may contribute to this gender effect, as increases in both endogenous and exogenous progesterone improved selective aspects of EI. Copyright © 2014 John Wiley & Sons, Ltd.

The epidemic of opioid use disorder (OUD) directly affects millions of women of child-bearing age. Unfortunately, parenting behaviors - among the most important processes for human survival - are vulnerable to the effects of OUD. The standard of care for pregnant women with OUD is opioid maintenance therapy (OMT), of which the primary objective is to mitigate addiction-related stress. The aim of this review is to synthesize current information specific to pregnancy and parenting that may be affected by OUD. We first summarize a model of the parental brain supported by animal research and human neuroimaging. We then review animal models of exogenous opioid effects on parental brain and behavior. We also present preliminary data for a unifying hypothesis that may link different effects of exogenous opioids on parenting across species and in the context of OMT. Finally, we discuss future directions that may inform research and clinical decision making for peripartum women with OUD.

Currently, no FDA-approved medication exists for the treatment of cocaine use disorder. Furthermore, as women become increasingly more at risk for the consequences of cocaine addiction, the need to establish better-tailored treatment medications is paramount. We examine the effects of the alpha2 adrenergic agonist, guanfacine HCl, on responses to stress and drug cue in a group of cocaine-dependent men and women who also abuse alcohol and nicotine. Forty early abstinent treatment-seeking cocaine-dependent males and females were randomly assigned to receive either daily placebo (12 M/7 F) or guanfacine (2 or 3 mg) (15 M/6 F) for 3 weeks. In week 4, they participated in a laboratory experiment and were exposed to three 10-min guided imagery conditions (stress/stress, cue/cue, and stress/cue), one per day, consecutively in a random, counterbalanced order. Craving, negative emotion, anxiety, and cardiovascular function were assessed at baseline, immediately following imagery exposure, and at various recovery time points. Guanfacine significantly attenuated cocaine craving, alcohol craving, anxiety, and negative emotion following exposure to all three imagery conditions in females, but not males. Guanfacine did, however, reduce sympathetic tone as well as stress and cue-induced nicotine craving and systolic blood pressure (SBP) in both males and females. These findings highlight sex-specific effects of guanfacine on drug craving, anxiety, and negative mood with significant effects in women and not men. The findings suggest further evaluation of guanfacine in the treatment of cocaine use disorder with a specific focus on sex differences in treatment response.

Cocaine dependence is a chronic stress state characterized by compulsive and uncontrollable drug seeking and drug use despite negative consequences. Moreover, compared with many other drugs of abuse, there are few efficacious medications that address the high rates of craving and cocaine use. Notably, the chronic use of cocaine is associated with robust adaptations to core neural stress systems that mediate stress sensitivity, anxiety pathophysiology and prefrontal regulatory function. As an alpha-2 adrenergic agonist, guanfacine’s ability to target such overlapping stress, reward, and anxiety pathophysiology suggests that it may be a useful long-term agent for attenuating the stress and cue-induced craving state in both women and men. This is supported by recent research findings from our own laboratory. Additionally, guanfacine’s improvement of regulatory mechanisms that are key to exerting cognitive and emotional control over drug-seeking behavior also suggests that guanfacine may be effective in reducing craving and relapse vulnerability in many drugs of abuse.

Background Increasing evidence suggests that levels of pro-inflammatory and anti-inflammatory cytokines are dysfunctional in alcohol dependence. Moreover, some initial findings demonstrate that these adaptations in peripheral inflammation may contribute to motivation for alcohol and problem drinking via possible direct effects or the indirect effects of stress responsivity. Importantly, the role of pro-inflammatory and anti-inflammatory cytokines in the progression from healthy to problem drinking is not well understood. The aim of this study was to assess whether alcohol-related peripheral immune system changes affect stress and alcohol cue-induced craving and anxiety and behavioral alcohol motivation and intake in the laboratory among problem drinkers compared with socially drinking controls. Methods Twenty-six problem drinkers and 38 moderate, social drinkers participated in a laboratory challenge procedure during which they were exposed to 3 personalized 5-minute imagery conditions (stress [S], relaxing [R], and alcohol cue [C]), followed by the “alcohol taste test” (ATT) as a measure of implicit alcohol motivation and intake, presented across 3 consecutive days, 1 per day in a randomized and counterbalanced order. Measures of tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), alcohol craving, and anxiety were assessed at baseline, immediately following imagery exposure and at discreet beer cue presentation in the ATT. Results Compared with moderate drinkers, problem drinkers demonstrated tonic attenuation of IL-6 and IL-1ra. In problem drinkers, these changes also accompanied elevated levels of stress- and cue-induced alcohol craving and anxiety and were predictive of provoked alcohol craving, behavioral alcohol motivation and intake, and severity of problem drinking. Conclusions Current findings indicate that selective immunosuppression in problem drinkers may play a key role in motivation for alcohol intake.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP - rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog) - had a genome-wide significant association with cognitive ageing (P=2.5 × 10 -8). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10 -6). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10 -8; females, P=1.66 × 10 -11; males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10 -11) and TOMM40 (rs11556505; P=2.45 × 10 -8) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear. © 2014 Macmillan Publishers Limited.

Objective To date, little research exists defining bio-behavioral adaptations associated with both marijuana abuse and risk of craving and relapse to other drugs of abuse during early abstinence.

Objective To evaluate how much the Addenbrooke's Cognitive Examination-revised (ACE-R) improves the estimate of cognitive ability from the Mini-Mental State Examination (MMSE) in people with Alzheimer disease (AD). Methods We examined itemized data in people with AD who were on the Scottish Dementia Research Interest Register drawn from eight centres across Scotland, covering 75% of the Scottish population. ACE-R items that comprise the MMSE and those that did not (non-MMSE items) were summed separately. We residualized MMSE total on non-MMSE total and vice versa to derive a measure of the variance unique to each. Results Five hundred and one (258 male, 243 female) participants, mean age 75.7 (range 52–94) years were on the register, of whom 329 (160 men, 169 women) had AD. Of those with AD, 309 had a mean MMSE of 20.5 and mean ACE-R of 57.5 measured with Pearson r = 0.92 between MMSE and ACE-R totals, and the regression equation ACE-R score = 3.0 × MMSE − 4.1. The unique non-MMSE items score correlated with ACE-R total r = 0.40 (16% of ACE-R variance). Conclusions The ACE-R and MMSE total scores are highly correlated. In this clinical sample of people with established AD, for an MMSE score of 24, the predicted ACE-R score was 67.9 with 95% confidence intervals of 61.6–75.4. The extra non-MMSE ACE-R items improve estimates of cognitive ability by 16%. Copyright © 2012 John Wiley & Sons, Ltd.

Objective: To investigate in older adults without dementia the relationships between socioeconomic status (SES) in childhood and magnetic resonance imaging (MRI)-derived brain volume measures typical of brain aging and Alzheimer’s disease (AD). Methods: Using a cross-sectional and longitudinal observation approach, we invited volunteers without dementia, all born in 1936, and who were participants in the 1947 Scottish Mental Survey, for MR brain imaging; 249 of 320 (77%) agreed. We measured whole brain and hippocampal volumes and recorded childhood SES history, the number of years of education undertaken, and adult SES history. Mental ability at age 11 years was recorded in 1947 and was also available. Results: Analysis shows a significant association between childhood SES and hippocampal volume after adjusting for mental ability at age 11 years, adult SES, gender, and education. Interpretation: A significant association between childhood SES and hippocampal volumes in late life is consistent with the established neurodevelopmental findings that early life conditions have an effect on structural brain development. This remains detectable more than 50 years later. ANN NEUROL 2012;71:653–660

Cocaine dependence is associated with high relapse rates, but few biological markers associated with relapse outcomes have been identified. Extending preclinical research showing a role for central brain-derived neurotrophic factor (BDNF) in cocaine seeking, we examined whether serum BDNF is altered in abstinent, early recovering, cocaine-dependent individuals and whether it is predictive of subsequent relapse risk.Serum samples were collected across three consecutive mornings from 35 treatment-engaged, 3-week-abstinent cocaine-dependent inpatients (17 males/18 females) and 34 demographically matched hospitalized healthy control participants (17 males/17 females). Cocaine-dependent individuals were prospectively followed on days 14, 30, and 90 posttreatment discharge to assess cocaine relapse outcomes. Time to cocaine relapse, number of days of cocaine use (frequency), and amount of cocaine use (quantity) were the main outcome measures.High correlations in serum BDNF across days indicated reliable and stable serum BDNF measurements. Significantly higher mean serum BDNF levels were observed for the cocaine-dependent patients compared with healthy control participants (p.001). Higher serum BDNF levels predicted shorter subsequent time to cocaine relapse (hazard ratio: 1.09, p.05), greater number of days (p.05), and higher total amounts of cocaine used (p = .05).High serum BDNF levels in recovering cocaine-dependent individuals are predictive of future cocaine relapse outcomes and may represent a clinically relevant marker of relapse risk. These data suggest that serum BDNF levels may provide an indication of relapse risk during early recovery from cocaine dependence.

Background: Stress, alcohol cues, and dysregulated stress responses increase alcohol craving and relapse susceptibility, but few pharmacologic agents are known to decrease stress- and cue-induced alcohol craving and associated stress dysregulation in humans. Here we report findings from a preliminary efficacy study of the alpha-1 receptor antagonist, prazosin, in modulating these relapse-relevant factors in alcohol-dependent individuals. Methods: Seventeen early abstinent, treatment-seeking alcohol-dependent individuals (12 men and 5 women) were randomly assigned to receive either placebo or 16 mg daily prazosin in a double-blind, placebo-controlled manner over 4 weeks. During week 4, all patients participated in a 3-day laboratory experiment involving 5-minute guided imagery exposure to stress, alcohol cue, and neutral-relaxing/control conditions, 1 exposure per day, on consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, negative emotion, cardiovascular measures, and plasma hypothalamic–pituitary–adrenal (HPA; cortisol, adenocorticotropic hormone) were assessed repeatedly in each session. Results: The prazosin group (n = 9) versus the placebo group (n = 8) showed significantly lower alcohol craving, anxiety, and negative emotion following stress exposure. The placebo group also showed significantly increased stress- and cue-induced alcohol craving, anxiety, negative emotion, and blood pressure (BP), as well as a blunted HPA response relative to the neutral condition, while the prazosin group showed no such increases in craving, anxiety, negative emotion, and BP, and no blunted HPA response to stress and alcohol cue exposure. Conclusions: Prazosin appears efficacious in decreasing stress- and cue-induced alcohol craving and may normalize the stress dysregulation associated with early recovery from alcoholism. Further research to assess the efficacy of prazosin in reducing alcohol craving and stress-related relapse risk is warranted.

General intelligence is an important human quantitative trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly associated with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. We estimate that 40% of the variation in crystallized-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequilibrium between genotyped common SNP markers and unknown causal variants. These estimates provide lower bounds for the narrow-sense heritability of the traits. We partitioned genetic variation on individual chromosomes and found that, on average, longer chromosomes explain more variation. Finally, using just SNP data we predicted B1% of the variance of crystallized and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, respectively). Our results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence. Molecular Psychiatry advance online publication, 9 August 2011; doi:10.1038/mp.2011.85

Objectives To describe the discovery and development of the Aberdeen 1921 and 1936 birth cohort studies. Study Design The Aberdeen birth cohort studies were started in 1998 when the Scottish Mental Survey archives of the Scottish Council for Research in Education were re-discovered and permissions granted to follow-up survivors born in 1921 or 1936 and then aged about 77 or 64 years and who had entered (or were about to enter) the age of greatest risk for Alzheimer's disease (AD). Main outcome measures Sources of attrition from the study, exposures to childhood adversity, nutritional, genetic and life style factors of possible relevance to extent of age-related cognitive decline and the timing of onset of dementia. Results By 2010, the feasibility of following up more than 75% of Scottish Mental Survey survivors living in the Aberdeen area without dementia was well-established, dementia ascertainment to age about 88 years was completed in the 1921 birth cohort and was underway in the 1936 born cohort. Conclusion These databases are available to other bone fide research groups wishing to test specific hypotheses that may either replicate their own findings or make best use of the data collected in the Aberdeen studies.

Objectives: to evaluate the role of childhood intelligence and white matter hyperintensities (WMH) in the prediction of the trajectory of fluid intelligence in healthy old people from age 78 to 81. Design: observational follow-up study from 1999 to 2002. Setting: a university teaching hospital in Aberdeen, UK. Participants: a total of 106 volunteers born in 1921, with childhood intelligence records at 11, recruited 1997–98 to a follow-up study. Measurements: participants underwent brain MRI in 1999–2000, to obtain measurements of brain WMH using Scheltens’ scale and a test of fluid intelligence (Raven’s Progressive Matrices) on three occasions between 1999 and 2002. Results: in a latent growth model, we found a significant association between childhood intelligence and the intercept, but not the slope, of fluid cognitive ability in late adulthood. Similarly, baseline WMH score was associated with the intercept of late life cognitive ability, but not the slope. Age at imaging was associated with slope but not intercept. There was no significant association between sex and intercept or slope of late life cognitive ability. Conclusions: results suggest that brain MRI measures of WMH (attributed to cerebrovascular disease) and childhood intelligence significantly contribute to late life fluid cognitive ability but not to the trajectory of age-related change in fluid intelligence. We also show that age is associated with the cognitive trajectory from 78 to 81 years, even within our narrow age range sample. This may be a consequence of the recruitment pattern, with those having greater WMH burden, and who subsequently declined, being recruited later in the study.

Objectives Organic solvent exposure may be associated with cognitive impairment in later life although the evidence for this association is inconsistent. This study sought to examine the association between organic solvent exposure and cognitive function in later life. Methods A prospective longitudinal study set in Aberdeen, Scotland examined 336 men and women born in 1936 who participated in the 1947 Scottish Mental Survey. Cognitive function at age 67 years was measured using the Trail Making Test B (TMT B), the Digit Symbol (DS) test, and the Auditory Verbal Learning Test (AVLT). Occupational hygienists reviewed occupational histories, blind to cognitive function, and estimated lifetime solvent exposures. Multiple regression analyses were employed to explore the association between solvent exposure and cognitive performance after adjustment for confounders. Results After adjusting for childhood IQ, smoking, alcohol and sex, the solvent exposed group took on average almost 10 s longer than the unexposed group to complete the TMT B, a highly significant difference. For the DS test, after adjusting for childhood IQ, smoking and gender, the exposed group scored on average two points lower than the unexposed group, which was again highly significant. There was no evidence of an effect for cumulative solvent exposure on the TMT B or DS test. For the AVLT there were no significant differences associated with exposure. Conclusions This study of subjects with generally low exposures, found no clear evidence of an association between solvent exposure and cognitive function.

Aims: Chronic alcohol and drug dependence leads to neuroadaptations in hypothalamic–pituitary–adrenal (HPA) and sympathetic adrenal medullary (SAM) stress systems, which impact response sensitivity to stress and alcohol cue and facilitates risk of relapse. To date, gender variations in these systems have not been fully assessed in abstinent alcohol-dependent individuals who also met criteria for cocaine abuse. Methods: Forty-two (21 M/21 F) early abstinent treatment-seeking substance-abusing (SA) men and women and 42 (21 M/21 F) healthy control (HC) volunteers were exposed to three 5-min guided imagery conditions (stress, alcohol/drug cue, neutral relaxing), presented randomly, one per day across three consecutive days. Alcohol craving and anxiety ratings were obtained as well as measures of heart rate (HR), blood pressure, plasma ACTH, cortisol, norepinephrine (NE) and epinephrine (EPI). Results: SA males showed increased ACTH and EPI basal tone compared with HC males and SA females. However, they demonstrated no increase in ACTH and cortisol levels following stress and alcohol cue imagery exposure compared to the neutral condition. SA females demonstrated a typically increased stress response in both measures. In addition, SA males showed no increase in cardiovascular response to either stress or cue, and no increase in catecholamine response to cue compared with their response to neutral imagery. Again, this dampening was not observed in HC males who produced significantly higher levels of cue-related HR and EPI, and significantly higher stress-related DBP. In contrast, SA females showed an enhanced ACTH and cortisol response to stress and cue compared with neutral imagery and this was not observed in the HC females. They also demonstrated a reduced increase in NE and EPI compared with both SA males and HC females as well as reduced HR compared with HC females. Conclusions: While SA males showed a generalized suppression of HPA, SAM system and cardiovascular markers following both stress and cue, SA women demonstrated a selective sympatho-adrenal suppression to stress only and an enhanced HPA response to both stress and cue. These gender variations are discussed in terms of their potential impact on relapse vulnerability and treatment outcome.

Extensive research indicates that chronic substance abuse disrupts stress and reward systems of the brain. Gender variation within these stress-system alterations, including the impact of sex hormones on these changes, may influence sex-specific differences in both the development of, and recovery from, dependency. As such, gender variations in stress-system function may also provide a viable explanation for why women are markedly more vulnerable than men to the negative consequences of drug use. This article therefore initially reviews studies that have examined gender differences in emotional and biophysiological changes to the stress and reward system following the acute administration of drugs, including cocaine, alcohol, and nicotine. The article then reviews studies that have examined gender differences in response to various types of stress in both healthy and drug-abusing populations. Studies examining the impact of sex hormones on these gender-related responses are also reported. The implications of these sex-specific variations in stress and reward system function are discussed in terms of both comorbid psychopathology and treatment outcome.

To explore the possible neural foundations of individual differences in intelligence test scores, we examined the associations between Raven's Matrices scores and two tasks that were administered in a functional magnetic resonance imaging (fMRI) setting. The two tasks were an n-back working memory (N = 37) task and inspection time (N = 47). The subjects were members of the Aberdeen Birth Cohort 1936, aged in their mid–late 60s when tested for this study. Performance on both tasks was correlated significantly with scores on Raven's Matrices. In the inspection time task there were regions with significant correlations between the neural activity (BOLD response) and performance but not between BOLD response and scores on Raven's Matrices. In the working memory task there were no significant correlations between BOLD response and either performance or scores on Raven's Matrices. Moreover, there was almost no mediation of the Raven's Matrices versus n-back and inspection time scores correlations by the respective BOLD response. These findings partially replicate important aspects of a prominent report in this field [Gray, J.R., Chabris, C.F., & Braver, T.S. (2003). Neural mechanisms of general fluid intelligence. Nature Neuroscience, 6, 316–322.], but have also extended the those finding into both a unique population and a novel functional task.

Chronic alcohol abuse is associated with changes in stress and reward pathways that could alter vulnerability to emotional stress and alcohol craving. This study examines whether chronic alcohol abuse is associated with altered stress and alcohol craving responses. Treatment-engaged, 28-day abstinent alcohol-dependent individuals (ADs; 6F/22M), and social drinkers (SDs; 10F/18M) were exposed to a brief guided imagery of a personalized stressful, alcohol-related and neutral-relaxing situation, one imagery condition per session, presented in random order across 3 days. Alcohol craving, anxiety and emotion ratings, behavioral distress responses, heart rate, blood pressure, and salivary cortisol measures were assessed. Alcohol patients showed significantly elevated basal heart rate and salivary cortisol levels. Stress and alcohol cue exposure each produced a significantly enhanced and persistent craving state in alcohol patients that was marked by increased anxiety, negative emotion, systolic blood pressure responses, and, in the case of alcohol cue, behavioral distress responses, as compared to SDs. Blunted stress-induced cortisol responses were observed in the AD compared to the SD group. These data are the first to document that stress and cue exposure induce a persistent negative emotion-related alcohol craving state in abstinent alcoholics accompanied by dysregulated HPA and physiological arousal responses. As laboratory models of stress and negative mood-induced alcohol craving are predictive of relapse outcomes, one implication of the current data is that treatments targeting decreases in stress and alcohol cue-induced craving and regulation of stress responses could be of benefit in improving alcohol relapse outcomes.

Evidence for an inverse relation between dietary intake of n-3 polyunsaturated fatty acids (PUFAs) and age-related cognitive decline is inconsistent. This inconsistency may arise because the relation is present only in the absence of the apolipoprotein E epsilon4 (APOE epsilon4) allele.We aimed to determine the contribution of erythrocyte n-3 PUFA content to cognitive aging in the presence or absence of the APOE epsilon4 allele.We followed up 120 volunteers, born in 1936, at approximate ages of 64, 66, and 68 y. Their intelligence quotient at 11 y old was available. At first follow-up, we determined APOE genotype and measured the PUFA composition of erythrocyte membranes. Six cognitive tests were administered at all follow-ups. We related cognitive performance at approximately 64 y old and cognitive changes from approximately 64 to approximately 68 y old to erythrocyte n-3 PUFA composition on recruitment and to APOE epsilon4 allele status.Total n-3 PUFA and docosohexaenoic acid concentrations were associated with benefits for cognition at approximately 64 y old and from approximately 64 to approximately 68 y old. After adjustment for sex, APOE epsilon4 status, and intelligence quotient at 11 y old, the effects associated with total n-3 PUFA remained significant. Cognitive benefits were associated with higher erythrocyte n-3 PUFA content but were significant only in the absence of the APOE epsilon4 allele.These data are evidence of a gene x environment interaction for cognitive aging. They are relevant to the analysis of trials of n-3 PUFA supplements in cognitive aging and dementia prevention, and they support heterogeneity in cognitive aging and, possibly, in Alzheimer disease.

A significant amount of neurobiological research regarding the development of alcohol use disorders (AUDs) has focused on alcohol-related activation and long-term alterations in the mesocortical dopaminergic reward pathways. However, alcohol does not only interact with brain reward systems. Many of its acute and chronic effects may be related to allostatic adaptations in hypothalamic and extrahypothalamic stress regulation pathways. For example, acute binge intoxication is associated with hypothalamically driven increases in blood cortisol, norepinephrine, and sex steroid metabolite levels. This may contribute to the development of mesocortical sensitization to alcohol. Furthermore, chronic alcohol exposure is associated with systemic dysregulation of the hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and sex steroid systems. This dysregulation appears to manifest as neuroendocrine tolerance. In this review, we first summarize the literature suggesting that alcohol-induced alterations in these hypothalamic systems influence craving and contribute to the development of AUDs. We note that for women, the effects of alcohol on these neuroendocrine stress regulation systems may be influenced by the rhythmic variations of hormones and steroids across the menstrual cycle. Second, we discuss how changes in these systems may indicate progression of AUDs and increased risk of relapse in both sexes. Specifically, neuroendocrine tolerance may contribute to mesocortical sensitization, which in turn may lead to decreased prefrontal inhibitory control of the dopaminergic reward and hypothalamic stress systems. Thus, pharmacological strategies that counteract alcohol-associated changes in hypothalamic and extrahypothalamic stress regulation pathways may slow the development and progression of AUDs.

The direct-weighted Schedule for the Evaluation of Individual Quality of Life, Direct Weighting (SEIQoL-DW) is an individualised measure of QoL that has been little used in very elderly people. We administered SEIQoL-DW during Wave 5 of the Aberdeen Birth Cohort 1921 Study (ABC1921) and sought statistical correlations with other variables in the data set. ABC1921 participants had been IQ-tested in 1932 at age 11. Since 1997, data about cognition, mental/physical function, personality, health, and socioeconomic status have been gathered in five waves of investigations. Ninety-six out of 98 individuals, mean age 82.2, completed the SEIQoL-DW. Health, family, relationships, finances and social pastimes were the commonest cues nominated, but age/gender differences existed. The mean SEIQoL-DW score (74.0) was significantly lower than in an approximately 60% sample from Wave 3, the fall being greater in men. Variables statistically associated with Wave 5 SEIQoL-DW usually reflected current rather than past status [including Short-Form 36 Health Survey (SF-36) components and depression], although there were weaker correlations with years of education, housing in childhood, conscientiousness, and IQ in 1998. SEIQoL-DW proved feasible and acceptable in community-dwelling octogenarians. Recent (i.e. statelike) rather than early or long-standing (i.e. traitlike) influences appeared to have the greater effect on QoL.

Social support is associated with health in old age. However, it is unclear whether this association is because social support helps maintain health or because people who are healthier are also advantaged in other ways (cognitive ability, education, wealth etc.) and thus have better access to social support. To investigate possible causal direction, we examined social support in later life in relation to cognitive ability in childhood (11 years) and later life (64 years). Our participants were 266 adults aged about 64 years (132 men, 134 women) recruited to the Aberdeen Birth Cohort 1936 study. Higher childhood cognitive ability, but not cognitive ability in later life, was associated with receiving less practical and emotional support, and being less satisfied with the support received. This pattern of results suggests that the relationship between cognition and social support is determined early in life and continues into later life.

Rationale Prior research has shown that cocaine dependence is associated with dysfunction of brain systems involved in emotions and motivational states. Objectives To examine whether difficulties in emotion regulation are associated with early cocaine abstinence using the recently validated Difficulties in Emotion Regulation Scale (DERS). Method Recently abstinent treatment-seeking cocaine patients (n = 60) completed the DERS during their first week of inpatient treatment and at discharge (3–4 weeks later), and scores were compared with community controls (n = 50). Results Compared with controls, cocaine-dependent individuals reported difficulties relating to understanding emotions, managing emotions and impulse control in the first week of abstinence. With continued abstinence, cocaine-dependent individuals showed continued difficulties only in impulse control. Conclusion Cocaine-dependent individuals report emotion regulation difficulties, particularly during early abstinence. Additionally, protracted distress-related impulse control problems suggest potential relapse vulnerability.

Chronic exposure to cocaine is associated with neuroadaptions in stress and reward circuits that may increase susceptibility to relapse. We examined whether there are alterations in stress response and craving in abstinent cocaine-dependent individuals compared with a demographically matched group of non-addicted socially drinking community controls. Forty treatment-engaged abstinent cocaine patients (17F/23M) and 40 controls (19F/21M) were exposed to a brief 5 min guided imagery of individually calibrated stressful situations, personal drug/alcohol-related situation and a neutral-relaxing situation, one imagery per session, presented in random order. Craving, anxiety, emotion rating scales, and physiological measures were assessed. Cocaine patients reported significantly higher and more persistent stress- and cue-induced drug/alcohol craving, negative emotions, and physiological responses compared with social drinkers. In cocaine patients, stress- and cue-induced drug craving was accompanied by increased anger, fear, sadness, heart rate, and SBP. Controls reported minimal stress-induced craving and only increases in anxiety and SBP during stress exposure. Cue-induced alcohol craving was accompanied only by an increase in relaxed state. Females reported increased stress-induced anxiety and sadness compared with males, while males were emotionally and physiologically more reactive in the cue condition. These findings are the first to document functional alterations in stress- and reward-related affect and physiology in recently abstinent cocaine patients that is marked by an enhanced sensitivity to stress- and drug-related cue exposure. These data suggest that recovery from chronic cocaine abuse could be hampered by a hyper-responsive stress- and drug-craving state that increases cocaine relapse susceptibility.

Lower childhood cognitive ability may be a risk factor for greater cognitive decline in late life and progression to dementia. To assess variation in age-related cognitive change, it is helpful to have valid measures of cognitive ability from early life. Here, we examine the relation between childhood intelligence and cognitive change in later life in two samples, one born in 1921 and the other in 1936. All participants completed the same test of mental ability (one of the Moray House Test series) at age about 11 years, and were re-examined on Raven’s Progressive Matrices at age 77 (1921-born) or age 64 (1936-born). Where possible, the 1921 sample was re-tested at the age of about 80 years old and the 1936 sample re-tested at about 66 years. After taking into account various covariates, including sex, education and occupation, childhood intelligence was a significant predictor of cognitive change in later life. Results were in the direction that participants with lower childhood mental ability experienced relatively greater cognitive decline, whereas those of higher childhood mental ability showed improved performance. This result suggests that higher premorbid cognitive ability is protective of decline in later life.

Dopaminergic neurotransmission in the pre-frontal cortex (PFC) contributes to individual cognitive differences in animals and humans. Catechol-O-methyltransferase (COMT) influences dopamine concentration in the PFC. Functional variation in the human COMT gene occurs at a single nucleotide polymorphism (SNP)--472G>A--that results in a valine (Val) to methionine (Met) amino acid substitution (Val158Met). The Met/Met form is less active resulting in higher dopamine concentrations and thus may enhance cognitive function. We applied repeated measures mixed general linear modelling over three waves between ages 64 and 68 years to optimise cognitive phenotype characterisation in a cohort of 473 community volunteers who had validated childhood IQ data. After adjusting for childhood IQ, wave of testing and specific test type, COMT Val158Met genotype polymorphism had a significant overall effect on cognition (F(2,935.7)=7.92, p

Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well. The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several measures of IQ. Five independent samples were used, totaling 2393 subjects, including both family-based and population-based datasets. Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype. © 2007 Oxford University Press.

Previously we reported that smoking is associated with a small relative decline in cognition from childhood to old age. In this study we perform confirmatory analyses on a further wave of data collected from 298 of the participants, all with age 11 IQ scores, at age 66 years, 2 years after the original observations. Non-smokers scored a mean 4.9 memory test and 2.6 information processing speed test points and ex-smokers 3.5 memory test and 1.9 information processing speed test points higher than current smokers respectively over the two waves of testing, equivalent to 4–8% of mean test scores, adjusted for the effects of childhood IQ. Across tests a 100 l/min higher Peak Expiratory Flow Rate was associated with a 3–4% higher test score at ages 64 and 66 years. These data confirm the adverse effect of smoking on information processing speed, and provide new evidence for a similar adverse effect on memory for people in their mid-sixties.

Objectives Fluctuations in progesterone levels during the menstrual cycle have been shown to affect physiological and subjective effects of cocaine. Furthermore, our laboratory has demonstrated that following drug-cue exposure, cocaine dependent women with high levels of circulating progesterone display lower diastolic and systolic blood pressure responses and report lower levels of anxiety and drug craving compared to cocaine dependent women with low levels of progesterone. In the current study we examined the role of the progesterone derived neuroactive steroid allopregnanolone (ALLO) on stress arousal, inhibitory control and drug craving in cocaine dependent subjects. Methods Plasma levels of ALLO were measured using GC/MS in 46 treatment-seeking cocaine dependent men and women on day 5 of a 7-day treatment regimen of micronized progesterone (15M/8F) (400 mg/day) or placebo (14M/9F) administered in a double blind, randomized manner. As a control, levels of the testosterone derived neurosteroid androstanediol (ADIOL) were also measured. All subjects participated in laboratory sessions on days 5–7 of progesterone/placebo administration in which they were exposed to a series of 5-min personalized guided imagery of either a stressful situation, cocaine use or of a neutral setting and dependent variables including subjective craving, mood, Stroop task as a measure of inhibitory control performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO level and levels of dependent variables compared between ALLO groups. Results Progesterone relative to placebo significantly increased ALLO levels with no sex differences. There were no effects of micronized progesterone on the testosterone derived ADIOL. Individuals in the high versus the low ALLO group showed decreased levels of cortisol at baseline, and a higher cortisol response to stress; higher positive mood scores at baseline and improved Stroop performance in the drug-cue and stress conditions, and reduced cocaine craving across all imagery conditions. Conclusions As expected, cocaine dependent individuals administered progesterone showed significantly higher ALLO plasma levels. High levels of ALLO appeared to normalize basal and stress response levels of cortisol, decrease cocaine craving and also contribute to improvements in positive emotion and Stroop performance in response to stress and drug-cue exposures. These findings suggest that the neuroactive steroid ALLO plays a significant role in mediating the positive effects of progesterone on stress arousal, cognitive performance and drug craving in cocaine dependence.

Cognitive reserve is a hypothetical concept introduced to explain discrepancies between severity of clinical dementia syndromes and the extent of dementia pathology. We examined cognitive reserve in a research programme that followed up a non-clinical sample born in 1921 or 1936 and IQ-tested age 11 years in 1932 or 1947. Structural MRI exams were acquired in about 50% of the sample from whom a subsample were recruited into an additional fMRI study. Here, we summarise findings from seven inter-related studies. These support an understanding of cognitive reserve as a balance between positive life course activity-driven experiences and the negative effects of brain pathologies including cerebrovascular disease and total and regional brain volume loss. Hypothesised structural equation models illustrate the relative causal effects of these positive and negative contributions. Cognitive reserve is considered in the context of choice of interventions to prevent dementia and the opposing effects of cerebrovascular disease and Alzheimer like brain appearances.

A polymorphism (Val66Met) in the gene encoding brain-derived neurotrophic factor (BDNF) has previously been associated with impaired hippocampal function and scores on the Logical Memory subtest of the Wechsler Memory Scale-Revised (WMS-R). Despite its widespread expression in the brain, there have been few studies examining the role of BDNF on cognitive domains, other than memory. We examined the association between BDNF Val66Met genotype and non-verbal reasoning, as measured by Raven's standard progressive matrices (Raven), in two cohorts of relatively healthy older people, one aged 79 (LBC1921) and the other aged 64 (ABC1936) years. LBC1921 and ABC1936 subjects had reasoning measured at age 11 years, using the Moray House Test (MHT), in the Scottish Mental Surveys of 1932 and 1947, respectively. BDNF genotype was significantly associated with later life Raven scores, controlling for sex, age 11 MHT score and cohort (P = 0.001). MHT, Verbal Fluency and Logical Memory scores were available, in later life, for LBC1921 only. BDNF genotype was significantly associated with age 79 MHT score, controlling for sex and age 11 MHT score (P = 0.016). In both significant associations, Met homozygotes scored significantly higher than heterozygotes and Val homozygotes. This study indicates that BDNF genotype contributes to age-related changes in reasoning skills, which are closely related to general intelligence.

The aim of this study was to assess the reliability of salivary cortisol as a measure of hypothalmic–pituitary–adrenal (HPA) axis function in cocaine dependent individuals. Saliva and total plasma samples were collected from 49 abusers on 3 testing days in the morning, across eight time points per day. Significant associations between saliva and plasma cortisol were observed across all time points collapsed across 3 days in both men and women. These moderately significant correlations suggest that salivary measurements represent a stable, non-invasive and broad indicator of HPA axis functioning in cocaine dependent individuals.