Oxytocin, PTSD, and sexual abuse are associated with attention network intrinsic functional connectivity.

Childhood maltreatment is linked to Posttraumatic Stress Disorder (PTSD) in adulthood. Neural attention network function contributes to resilience against PTSD following maltreatment; oxytocin administration alters functional connectivity differentially among resilient to PTSD groups. The present study examined intrinsic connectivity between ventral and dorsal neural attention networks (VAN and DAN) to clarify the nature of dysfunction versus resilience in the context of maltreatment-related PTSD, and to explore differential dysfunction related to varied aspects of maltreatment. Oxytocin administration was examined as a factor in these relationships. Resting-state functional connectivity data were collected from 39 adults with maltreatment histories, with and without PTSD, who were randomly assigned to receive oxytocin or placebo. We found that PTSD and sexual abuse (SA) were associated with reduced VAN-DAN connectivity. There were no significant effects with regard to physical abuse. Oxytocin was associated with greater VAN-DAN connectivity strength. These preliminary findings suggest dysfunction within attentional systems in PTSD, as well as following SA. Further, oxytocin may help ameliorate attentional neurocircuitry dysfunction in individuals with PTSD and those with maltreatment histories.

Effects of intranasal oxytocin on threat- and reward-related functional connectivity in men and women with and without childhood abuse-related PTSD.

Novel treatments that target neurobiological alterations associated with childhood trauma, particularly among those with posttraumatic stress disorder (PTSD), could mitigate negative outcomes for these at-risk individuals. PTSD is characterized by abnormalities within the brain's salience network and reward circuitry, which are modulated by intranasal oxytocin. Using a double-blind, randomized, placebo-controlled crossover design, we tested whether intranasal oxytocin (24 international units) influenced functional coupling of the amygdala with the anterior insula (AI), dorsal anterior cingulate cortex, and nucleus accumbens in response to implicitly presented fearful, angry, and happy faces among childhood trauma-exposed individuals with (n = 16, 9 women) and without PTSD (n = 18, 12 women). Psychophysiological interaction analyses revealed that oxytocin effects were limited to amygdala-AI connectivity in the fear condition, distinct for men and women, and not impacted by PTSD diagnosis. In response to fear faces, oxytocin reduced left amygdala-left AI connectivity for women but not men; reduced left amygdala-right AI connectivity among women, but increased this connectivity in men; and reduced right amygdala-right anterior insula connectivity for men, but increased it for women. Results suggest that intranasal oxytocin modulates threat salience among childhood trauma-exposed individuals and that these effects vary as a function of gender and hemisphere.

Effects of oxytocin on working memory and executive control system connectivity in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a chronic, debilitating condition for which effective medications are scant and little is known about neural correlates of risk versus resilience. Oxytocin is a hypothalamic neuropeptide that has demonstrated promise in modulating neurobiological and behavioral correlates of PTSD. Cognitive deficits in areas such as working memory and executive control are highly prevalent among individuals with PTSD and oxytocin might modulate these impairments in individuals with PTSD. Using a double-blind, placebo-controlled design, this study employed functional MRI (fMRI) and the n-back working memory task to examine the effects of oxytocin (24 IU) versus placebo on working memory and dorsolateral prefrontal cortex (DLPFC) connectivity among individuals with PTSD (n = 16) as compared with a trauma-exposed control group (n = 18). Results indicate that individuals with PTSD on oxytocin performed better in the 2-back condition of the n-back task compared with individuals with PTSD on placebo. Results also indicate that connectivity between DLPFC and anterior cingulate increased in the 2-back condition among individuals with PTSD on oxytocin as compared with placebo. These findings provide preliminary evidence of an effect of oxytocin on working memory among individuals with PTSD and insights into the neurobiological mechanisms underlying this association. Future studies are necessary to understand the mechanisms responsible for working memory deficits in PTSD and to examine the potential of oxytocin for use as a treatment for PTSD. (PsycINFO Database Record

Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: A randomized, placebo-controlled pilot trial.

Posttraumatic stress disorder (PTSD) is a chronic, debilitating condition for which Prolonged Exposure (PE) therapy is highly efficacious. However, for some individuals, premature dropout and residual PTSD symptoms remain obstacles. The neuropeptide oxytocin is a promising candidate to enhance PE due to its ability to enhance 1) prosocial cognition and behavior, which are theorized to promote positive working alliance, and 2) extinction learning, which is the central mechanism of action underlying successful PE treatment. Despite a robust theoretical rationale, no studies to date have combined evidence-based psychotherapy for PTSD with oxytocin. This randomized, placebo-controlled, double-blind pilot trial examined the feasibility, safety, and preliminary efficacy of augmenting PE with oxytocin. Participants were 17 individuals with diverse index traumas. Participants self-administered intranasal oxytocin (40 IU) or matching placebo 45 min prior to each weekly PE therapy session. One adverse event occurred in the placebo group and three individuals dropped out (17.6%; 2 oxytocin group and 1 placebo group). The oxytocin group demonstrated lower PTSD and depression symptoms during PE, and had higher working alliance scores, although these differences did not reach statistical significance. Although preliminary, the findings support the feasibility of oxytocin combined with PE. Adequately powered studies are necessary to determine whether oxytocin enhances PE treatment outcomes and to examine potential mechanisms, such as accelerating extinction learning, enhancing early response, and preventing premature dropout. NCT03238924.

Impact of endogenous progesterone on reactivity to yohimbine and cocaine cues in cocaine-dependent women.

BACKGROUND AND OBJECTIVE: Data from clinical and preclinical models of relapse suggest that progesterone attenuates cocaine-seeking behavior. In a recent study, we found that cocaine-dependent women reported greater subjective responses to cues that were preceded by a stressor than cocaine-dependent men. The objective of this study was to examine the impact of endogenous progesterone on the subjective and endocrine responses to a drug-paired cue that was preceded by a stressor in cocaine-dependent women. METHODS: Cocaine-dependent women with low (<4ng/ml; n=16) and high (≥4ng/ml; n=9) plasma progesterone levels received either the alpha-2 adrenergic receptor antagonist yohimbine (21.6mg) or placebo before each of two cocaine-cue exposure sessions. Participants were tested under both conditions in a counterbalanced, double-blind fashion. Data were collected after study drug administration, immediately and at 5, 30, and 60min after the cue. RESULTS: The anxiety response to the cue was differentially modified by progesterone levels under the two administration conditions (condition×progesterone level interaction, F1,23=9.8, p=0.005). Progesterone levels also modified the craving response to the cue differently under the placebo condition as compared to the yohimbine condition (condition×progesterone level interaction, F1,23=13.9, p=0.001). In both cases, high progesterone levels attenuated craving and anxiety response to the cue following yohimbine administration. There was no effect of progesterone levels on salivary cortisol or dehydroepiandrosterone under the placebo condition or under the yohimbine condition. CONCLUSIONS: These preliminary data suggest that high levels of endogenous progesterone attenuate subjective responses to drug-cues that are preceded by a stressor. Importantly, these data support a growing literature demonstrating the protective effects of progesterone on the vulnerability to cocaine relapse in women.

Network Analysis of Intrinsic Functional Brain Connectivity in Male and Female Adult Smokers: A Preliminary Study.

Background: The goal of this study was to conduct a preliminary network analysis (using graph-theory measures) of intrinsic functional connectivity in adult smokers, with an exploration of sex differences in smokers. Methods: Twenty-seven adult smokers (13 males; mean age = 35) and 17 sex and age-matched controls (11 males; mean age = 35) completed a blood oxygen level-dependent resting state functional magnetic resonance imaging experiment. Data analysis involved preprocessing, creation of connectivity matrices using partial correlation, and computation of graph-theory measures using the Brain Connectivity Toolbox. Connector hubs and additional graph-theory measures were examined for differences between smokers and controls and correlations with nicotine dependence. Sex differences were examined in a priori regions of interest based on prior literature. Results: Compared to nonsmokers, connector hubs in smokers emerged primarily in limbic (parahippocampus) and salience network (cingulate cortex) regions. In addition, global influence of the right insula and left nucleus accumbens was associated with higher nicotine dependence. These trends were present in male but not female smokers. Conclusions: Network communication was altered in smokers, primarily in limbic and salience network regions. Network topology was associated with nicotine dependence in male but not female smokers in regions associated with reinforcement (nucleus accumbens) and craving (insula), consistent with the idea that male smokers are more sensitive to the reinforcing aspects of nicotine than female smokers. Implications: Identifying alterations in brain network communication in male and female smokers can help tailor future behavioral and pharmacological smoking interventions. Male smokers showed alterations in brain networks associated with the reinforcing effects of nicotine more so than females, suggesting that pharmacotherapies targeting reinforcement and craving may be more efficacious in male smokers.

Individualized real-time fMRI neurofeedback to attenuate craving in nicotine-dependent smokers.

BACKGROUND: Cue-induced craving plays an important role in relapse, and the neural correlates of cue-induced craving have been elucidated using fMRI. This study examined the utility of real-time fMRI (rtfMRI) neurofeedback to strengthen self-regulation of craving-related neural activation and cue-reactivity in cigarette smokers. METHODS: Nicotine-dependent smokers were randomized to rtfMRI neurofeedback or to a no-feedback control group. Participants completed 3 neuroimaging visits. Within each visit, an initial run during which smoking-related cues were used to provoke craving, an individualized craving-related region of interest (ROI) in the prefrontal cortex or anterior cingulate cortex was identified. In the rtfMRI group, activity from the ROI was fed back via a visual display during 3 subsequent runs while participants were instructed to reduce craving during cue exposure. The control group had an identical experience with no feedback provided. RESULTS: Forty-four nicotine-dependent smokers were recruited to participate in our study; data from the 33 participants who completed a 1-week follow-up visit were included in the analysis. Subjective craving ratings and cue-induced brain activation were lower in the rtfMRI group than in the control group. LIMITATIONS: As participants were not seeking treatment, clinical outcomes are lacking. CONCLUSION: Nicotine-dependent smokers receiving rtfMRI feedback from an individualized ROI attenuated smoking cue-elicited neural activation and craving, relative to a control group. Further studies are needed in treatment-seeking smokers to determine if this intervention can translate into a clinically meaningful treatment modality.

Impact of acute guanfacine administration on stress and cue reactivity in cocaine-dependent individuals.

BACKGROUND: Stress and drug-paired cues increase drug craving and noradrenergic activity in cocaine-dependent individuals. Thus, medications that attenuate noradrenergic activity may be effective therapeutic treatment options for cocaine-dependent individuals. OBJECTIVES: To examine the impact of acute administration of the α2 adrenergic receptor agonist guanfacine on responses to multiple risk factors for relapse in cocaine-dependent individuals. METHODS: In a double-blind, placebo-controlled study, cocaine-dependent individuals (n = 84), were randomized to receive either 2 mg guanfacine (n = 50) or placebo (n = 34). Within each treatment arm, subjects were randomized to either a stress (guanfacine n = 26; placebo n = 15) or a no-stress (guanfacine n = 24; placebo n = 19) group. Participants in the stress group performed the Trier Social Stress Test. Subjects in each group were exposed to a neutral cue and then to cocaine-related cues. Plasma cortisol and subjective responses were compared between the four groups. RESULTS: The no-stress guanfacine group reported greater craving in response to cocaine cues as compared to the neutral cue (p < 0.001). The guanfacine stress group reported greater subjective stress at the neutral cue than at baseline (p = 0.032). The cocaine cue increased subjective stress in the guanfacine (p < 0.001) no-stress group. There were no effects of guanfacine on cortisol levels in either the stress or no stress groups (all p > 0.70). CONCLUSION: This study found no effects of a single 2 mg dose of guanfacine on reactivity to stress and cues alone or on the interaction of stress and drug cues. In cocaine-dependent individuals an acute 2 mg dose of guanfacine may not be an effective therapeutic treatment strategy.

Right anterior insula connectivity is important for cue-induced craving in nicotine-dependent smokers.

The insula has been implicated in cue-induced craving and relapse in nicotine-dependent tobacco cigarette smokers. The aims of the present study were to identify brain regions that exhibit greater functional connectivity with the right anterior insula in response to smoking cues than to neutral cues and the role of functional connectivity between these regions in mediating cue-induced craving in healthy (free of axis I psychiatric disorders) nicotine-dependent tobacco cigarette smokers. Functional magnetic resonance imaging data were collected from 63 healthy nicotine-dependent smokers viewing blocks of smoking and neutral cues. Craving ratings were obtained after each block. A psychophysiologic interaction approach was used to identify regions that exhibited significantly greater functional connectivity with the right anterior insula (seed) during the smoking cues than during the neutral (corrected cluster thresholding, Z > 2.3, P = 0.05). Parameter estimates of the interaction effects from each region were regressed against the mean cue-induced craving scores. Significant task by seed interactions were observed in two clusters centered in the bilateral precuneus and left angular gyrus. The strength of connectivity between the right anterior insula and the precuneus, which is involved interoceptive processing and self-awareness, was positively correlated with the magnitude of the craving response to the smoking cues (r(2) = 0.15; P < 0.01). These data suggest that among smokers, cue-induced craving may be a function of connectivity between two regions involved in interoception and self-awareness. Moreover, treatment strategies that incorporate mindful attention may be effective in attenuating cue-induced craving and relapse in nicotine-dependent smokers.

Ovarian hormones and drug abuse.

There are significant gender differences in course, symptomology, and treatment of substance use disorders. In general data from clinical and preclinical studies of substance use disorders suggest that women are more vulnerable than men to the deleterious consequences of drug use at every phase of the addiction process. In addition data from epidemiologic studies suggest that the gender gap in the prevalence of substance use is narrowing particularly among adolescence. Therefore, understanding the role of estrogen and progesterone in mediating responses to drugs of abuse is of critical importance to women's health. In this review we will discuss findings from clinical and preclinical studies of (1) reproductive cycle phase; (2) endogenous ovarian hormones; and (3) hormone replacement on responses to stimulants, nicotine, alcohol, opioids, and marijuana. In addition, we discuss data from recent studies that have advanced our understanding of the neurobiologic mechanisms that interact with estrogen and progesterone to mediate drug-seeking behavior.

Yohimbine administration and cue-reactivity in cocaine-dependent individuals.

RATIONALE: Preclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations. OBJECTIVES: The objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women. METHODS: In a double-blind placebo-controlled cross-over study, cocaine-dependent men (n = 32), cocaine-dependent women (n = 30), control men (n = 32), and control women (n = 25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. RESULTS: Yohimbine increased ratings of anxiety both before (p < 0.001) and after (p = 0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p = 0.001). Yohimbine also significantly increased craving, compared with placebo (p < 0.05), following the cue presentation, and this effect was greater in women than men (gender by treatment interaction; p = 0.006). Yohimbine also increased salivary cortisol (p < 0.001) and dehydroepiandrosterone (p = 0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p < 0.001). CONCLUSIONS: Stress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions.

Association of elevated cytokines with childhood adversity in a sample of healthy adults.

OBJECTIVE: Childhood trauma has been associated adult stress-related disorders. However, little is known about physiologic alterations in adults with a history of early life trauma that do not have current psychiatric or medical diagnoses. In this study, the relationships between childhood adversity and cytokine and C-reactive protein (CRP) levels in healthy adults were examined. METHOD: Participants included men (n = 18) and women (n = 20) who did not meet DSM-IV criteria for Axis I psychiatric disorders or any major medical illness. Cytokine and CRP levels were obtained from baseline blood samples. Subjects completed the Early Trauma Inventory Self Report (ETI-SR). The primary outcomes included serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL1-ß), and CRP levels. In addition, the mean numbers of traumatic experiences (sexual, physical, emotional, general, and the summed total) were measured. RESULTS: Significant positive associations were found between the total ETI score and IL-6 (p = 0.05), IL1-ß (p < 0.05), and TNF-α (p = 0.01). Significant positive correlations were found between the number of general traumas and IL1-ß (p < 0.05), TNF-α (p < 0.05), and IL-6 (p < 0.01). Neither the total number of traumas nor any of the trauma subscales were significantly associated with CRP levels. CONCLUSIONS: The positive association between childhood trauma and basal cytokine levels supports the extant literature demonstrating the long-term impact of childhood trauma and stress on homeostatic systems. Importantly, this association was found in healthy adults, suggesting that these alterations may precede the development of significant stress-related psychiatric disorder or disease.

Psychoticism and neuroticism predict cocaine dependence and future cocaine use via different mechanisms.

BACKGROUND: Personality characteristics have been associated with cocaine use. However, little is known about the mechanisms through which personality could impact drug use. The present study investigated the cross-sectional and prospective relationships between personality dimensions (i.e., impulsivity, neuroticism) and problematic cocaine use. Reactivity to a pharmacological stressor as a potential mediator of the relationship between neuroticism and future cocaine use was also examined. METHODS: Participants were 53 cocaine-dependent individuals and 47 non-dependent controls. Subjects completed the Eysenck Personality Questionnaire (EPQ) at baseline and were administered i.v. corticotrophin releasing hormone (CRH; 1 µg/kg). Cocaine use in the 30 days following CRH administration was measured. RESULTS: Cocaine-dependent individuals had higher scores on the psychoticism (i.e., impulsivity, aggression; p=0.02) and neuroticism (p<0.01) scales of the EPQ than non-dependent controls. Cocaine-dependent individuals also had a greater subjective stress response to CRH than controls (p<0.01). Cocaine-dependent individuals with elevated psychoticism used significantly more cocaine over the follow-up period (p<0.05), whereas individuals with elevated neuroticism trended towards using cocaine more frequently over the follow-up (p=0.07). Finally, there was a trend for an indirect effect of neuroticism on frequency of cocaine use through subjective reactivity to CRH. CONCLUSIONS: The findings extend past research on the association between personality and cocaine use, and suggest that motives for cocaine use may systematically vary across personality characteristics. Moreover, tailoring therapeutic interventions to individuals' personalities may be an area that warrants further investigation.

Influence of cocaine dependence and early life stress on pituitary-adrenal axis responses to CRH and the Trier social stressor.

Long-term changes in the hypothalamic-pituitary-adrenal (HPA) axis as a result of early life stress could be related to the development of substance use disorders during adulthood. In this study, the neuroendocrine, physiologic (HR), and subjective responses to corticotropin releasing hormone (CRH) and the Trier Social Stress Task (TSST) in individuals with cocaine dependence, with (n=21)/without early life stress (n=21), non-dependent individuals with early life stress (n=22), and a control group were examined (n=21). CRH increased cortisol and ACTH levels in all groups. However, a significant effect of early life stress on ACTH was observed indicating that the increase in ACTH was greatest in subjects with a history of childhood stress. Post hoc analysis indicated the early life stress/non-cocaine dependent individuals exhibited significantly higher levels of ACTH as compared to the early life stress/cocaine-dependent group. Despite the elevated ACTH response there was no difference between the groups in the cortisol response to CRH. The TSST produced a significant elevation in ACTH and cortisol all study groups. No significant group differences were observed. The subjective stress and peak heart rate responses to the TSST were greatest in cocaine-dependent subjects without early life stress. In response to CRH, subjective stress and craving were positively correlated in cocaine-dependent subjects regardless of early life stress history, while stress and craving following the TSST were correlated only in cocaine-dependent subjects without a history of early life stress. Findings support previous studies demonstrating that subjects with a history of childhood adversity exhibit elevated ACTH and blunted cortisol levels in response to stress. In contrast, HR and subjective stress in response to the TSST were greatest in cocaine-dependent subjects without a history of early life stress, suggesting that childhood adversity may desensitize autonomic and subjective responding to social stress in adults with cocaine dependence.

Reactivity to laboratory stress provocation predicts relapse to cocaine.

BACKGROUND: Cocaine dependence is a chronic relapsing disorder characterized by periods of abstinence and high rates of return to drug using behavior. Elevated levels of stress have been associated with relapse to cocaine; however, the nature of this association is not well understood. METHODS: The relationship between reactivity to three human laboratory provocations and relapse to cocaine was investigated. Participants were 53 cocaine-dependent individuals who were admitted for a 2-day inpatient stay during which a psychosocial provocation (i.e., the Trier Social Stress Task), a pharmacological provocation (i.e., administration of 1 microg/kg corticotrophin releasing hormone; CRH), and a drug cue exposure paradigm were completed. Adrenocortico-trophic hormone (ACTH), cortisol, heart rate, and subjective cocaine craving and stress were assessed at baseline and at multiple time points post-task. Participants' cocaine use was monitored for approximately 1 month following testing. RESULTS: The majority (72.3%) of participants relapsed to cocaine during the follow-up period. In response to the CRH and drug cue exposure, elevated subjective craving and stress were significant predictors of cocaine use during follow-up. In response to the Trier, attenuated neuroendocrine responses were significant predictors of cocaine use. CONCLUSIONS: The findings provide further evidence of the ability of laboratory paradigms to predict relapse. The observed associations between stress reactivity and subsequent cocaine use highlight the clinical importance of the findings. Predictors of relapse may vary based on the type of provocation utilized. Interventions aimed at normalizing stress response, as measured using laboratory paradigms, may prove useful in relapse prevention.

Response to corticotropin-releasing hormone infusion in cocaine-dependent individuals.

CONTEXT: Corticotropin-releasing hormone (CRH), through the hypothalamic pituitary adrenal axis and other brain stress systems, is involved in the emotional dysregulation associated with cocaine dependence. Little is known about the response of cocaine-dependent individuals to CRH administration. OBJECTIVE: The primary objective was to examine the hypothalamic-pituitary-adrenal axis and the subjective and physiologic response to CRH in cocaine-dependent individuals and controls. DESIGN: A case-control study. SETTING: Subjects were admitted to a General Clinical Research Center for testing and abstinence was verified with a urine drug screening. PARTICIPANTS: Participants were male controls (n = 23), female controls (n = 24), cocaine-dependent men (n = 28), and cocaine-dependent women (n = 25). Individuals with dependence on other substances (except caffeine or nicotine) or with major depression, posttraumatic stress disorder, bipolar disorder, or psychotic or eating disorders were excluded. INTERVENTION: Subjects received 1 microg/kg of CRH intravenously. MAIN OUTCOME MEASURES: Primary outcomes included plasma corticotropin levels, cortisol levels, and heart rate and subjective measurements. RESULTS: Cocaine-dependent individuals exhibited higher stress (P < .001) and craving for CRH compared with controls. A positive correlation (r(s) = 0.51; P < .001) between stress and craving was found in cocaine-dependent subjects. Intravenous CRH elevated heart rates in all groups; however, cocaine-dependent women demonstrated a significantly higher heart rate at all time points (P = .05). Women had higher cortisol responses to CRH (P = .03). No effect of cocaine status was observed. The corticotropin response to CRH was independent of sex and cocaine dependence. Cortisol and corticotropin were positively correlated in the controls and cocaine-dependent men, but not in cocaine-dependent women (r(s) = 0.199; P = .4). CONCLUSIONS: There is an increased subjective and heart rate response to CRH and a relationship between stress and craving in cocaine-dependent individuals. The lack of difference in hypothalamic pituitary adrenal axis response between the cocaine-dependent and control groups suggests that the heart rate and subjective responses in the cocaine group may be mediated by sensitization of nonhypothalamic stress-responsive CRH systems.

Relationship between child abuse and adult smoking.

OBJECTIVE: A strong association between a history of child abuse and subsequent psychiatric disorders including substance use has been demonstrated. However, few studies have examined the relationship between child abuse and cigarette smoking in individuals without co-occurring psychiatric disorders. In this study, the relationship between severe childhood abuse and smoking were examined in a group of adults without significant psychopathology. METHODS: Participants (N = 57) represent the control group of a larger study of substance dependence. Participants were without major DSM-IV psychopathology, including substance use disorders, major depression, or posttraumatic stress disorder. The Early Trauma Inventory [20] assessed history of exposure to traumatic events prior to age 18. RESULTS: The majority of individuals with, as compared to without, a history of severe child abuse (79% vs. 47%, p = .02) were current cigarette smokers. The odds of smoking was four times as high in participants with versus without a severe childhood abuse history (OR = 4.0, p = 0.04). CONCLUSIONS: Although preliminary, the findings demonstrate a strong link between early childhood trauma and later adult cigarette smoking among individuals without significant substance use or other psychopathology.