PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Hum Brain Mapp. Author manuscript; available in PMC 2012 November 1.
Published in final edited form as:
PMCID: PMC3236497
NIHMSID: NIHMS330991

Sex Differences in Neural Responses to Stress and Alcohol Context Cues

Abstract

Stress and alcohol context cues are each associated with alcohol-related behaviors, yet neural responses underlying these processes remain unclear. The present study investigated the neural correlates of stress and alcohol context cue experiences and examined sex differences in these responses. Using functional magnetic resonance imaging, brain responses were examined while 43 right-handed, socially drinking, healthy individuals (23 females) engaged in brief guided imagery of personalized stress, alcohol-cue and neutral-relaxing scenarios. Stress and alcohol-cue exposure increased activity in the cortico-limbic-striatal circuit (p<.01, corrected), encompassing the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), left anterior insula, striatum and visuomotor regions (parietal and occipital lobe, and cerebellum). Activity in the right dorsal striatum increased during stress, while bilateral ventral striatum activity was evident during alcohol-cue exposure. Men displayed greater stress-related activations in the mPFC, rostral ACC, posterior insula, amygdala and hippocampus than women, whereas women showed greater alcohol-cue related activity in the superior and middle frontal gyrus (SFG/MFG) than men. Stress-induced anxiety was positively associated with activity in emotion modulation regions, including the medial OFC, ventromedial PFC, left superior-medial PFC and rostral ACC in men, but in women with activation in the SFG/MFG, regions involved in cognitive processing. Alcohol craving was significantly associated with the striatum (encompassing dorsal and ventral) in men, supporting its involvement in alcohol ‘urge’ in healthy men. These results indicate sex differences in neural processing of stress and alcohol-cue experiences, and have implications for sex-specific vulnerabilities to stress- and alcohol-related psychiatric disorders.

Keywords: Sex differences, Stress, Alcohol cue, Reward, Brain fMRI, Prefrontal Cortex

Introduction

Stress is a key vulnerability factor in psychiatric disorders (Cohen, et al. 2007; Sinha 2009b), and sex differences in the prevalence of mood and anxiety disorders and addiction have been documented (Becker, et al. 2007; Kessler, et al. 1993). In individuals with alcohol use disorders, stress and alcohol-related cues are important factors increasing alcohol craving and relapse risk (Sinha and Li 2007). In epidemiological samples, stress increases alcohol consumption (Dawson, et al. 2005; Grzywacz and Almeida 2008), and greater alcohol use was also reported after exposure to the 911 attacks in New York (Boscarino, et al. 2006).

Stress provokes defensive motivation and avoidant behaviors (Nachmias, et al. 1996), while social alcohol consumption is associated with appetitive motivation and approach behaviors (Lukas, et al. 1986; Robinson and Berridge 1993). The defensive and appetitive systems are two parallel systems with common, integrative components (Cacioppo, et al. 1999; Carver 2001), suggesting the presence of specific yet overlapping brain systems underlying these two systems.

Neuroimaging studies on stress and aversive processing have identified a specific corticostriatal-limbic circuitry including the medial prefrontal cortex (PFC), anterior cingulate cortex (ACC), hippocampus, amygdala and striatum (Lopez, et al. 1999; Sinha, et al. 2004; Zhou, et al. 2008). Recent evidence also indicates that alcohol taste cue (Filbey, et al. 2008) and intravenous injection of alcohol (Gilman, et al. 2008) reliably activates brain reward circuits, specifically mesocortico-striatal structures such as the PFC and ventral striatum in healthy social drinkers. The ventral striatum has been associated with reward processing (Schott, et al. 2008) and the amygdala is associated with stress response (Zhou, et al. 2008), with some evidence in reward processing (Garavan, et al. 2001). These data indicate that the coticostriatal-limbic regions may represent the core circuits involved in both stress and alcohol cue-related processing, but no previous research has directly compared neural circuits associated with these processes in humans.

Sex differences in stress responses have also been previously reported. Recent neuroimaging evidence indicates that compared to women, men showed greater stress-related brain responses in fronto-limbic areas, especially in the medial PFC, ACC, hypothalamus and amygdala (Goldstein, et al. 2010). Greater physiological responses to stress in men are consistent with behavioral and neuroendocrine studies. For example, men show greater stress-related negative emotion and aggression responses, more robust fear conditioning and higher cortisol responses than women (Jackson, et al. 2006; Kudielka and Kirschbaum 2005; Verona, et al. 2007), while women under stress show greater tendencies to rumination and negative cognition (Nolen-Hoeksema 1987). Further, men showed greater stress-related increases in alcohol craving and consumption than women (Lindquist, et al. 1997; Tamres, et al. 2002). While this literature suggests sex differences in responses to stress and alcohol-related behaviors, and there is some evidence of sex differences in neuroimaging of stress, no previous research has examined sex differences when directly comparing the neural responses to emotional stress and alcohol context cues in healthy individuals.

To clarify sex-specific neural responses to stress and alcohol context cues, the current study utilized individually calibrated, personally relevant, guided imagery scripts of stress and alcohol context cue that were compared to personalized neutral relaxing scripts. It is a widely used, ecologically valid method of emotion, stress and craving provocation in laboratory and in neuroimaging studies (for a review, Sinha 2009a). Based on the previously cited research, we hypothesized that in healthy individuals, both stress and alcohol cues would activate the prefrontal and ACC regions known to be involved in stress and reward modulation. Further compared to women, men would show greater neural responses to stress in corticostriatal limbic regions, especially in the mPFC, ACC and amygdala. In terms of self-reported anxiety and craving, we expected significantly elevated stress-induced anxiety and alcohol cue-induced craving from the baseline. However, we did not expect that stress-induced craving or alcohol-cue induced anxiety would be increased in healthy individuals based on previous studies (Fox, et al. 2008; Sinha, et al. 2009). As the striatum is involved in motivation for alcohol (Heinz, et al. 2004; Schneider, et al. 2001; Wrase, et al. 2007), we expected it to be associated with subjective alcohol craving. We also hypothesized that the stress circuit involving the medial PFC, ACC, and the amygdala would be associated with stress-induced anxiety.

Materials and Methods

Participants

Forty-three healthy individuals between the ages of 19 and 50 were recruited from the community via newspaper, web advertising and flyers. All participants were right-handed and reported light to moderate levels of alcohol consumption (up to 25 drinks per month). Over the course of 2-3 sessions, participants completed demographic, psychiatric, cognitive, drug use and self assessments. To ensure healthy physical function, a medical evaluation was conducted including laboratory testing of renal, hepatic, pancreatic, hematopoietic, and thyroid functions. Participants were excluded if they had the following: (a) a history of head trauma, (b) pregnancy, (c) use of psychoactive medication, (d) current or lifetime substance abuse or dependence and (e) current or lifetime history of neurological or psychiatric disorders (as assessed by the Structured Clinical Interview for DSM-IV). Women were scheduled to participate in the laboratory sessions during the follicular or luteal phases of their menstrual cycle (as determined by sex steroid hormone measurements) and were excluded if they reported irregular menstrual cycle or were taking hormonal birth control, to control for the possible influence of steroid hormonal fluctuations on stress responses (Kirschbaum, et al. 1999). All participants were asked to refrain from alcohol for at least 72 hours prior to the scanning session and breathalyzer and urine toxicology screening was used to confirm drug and alcohol abstinence for each assessment session and on scanning day. Upon completion of the assessments, they participated in a 1.5 hour functional magnetic resonance imaging (fMRI) session. The Human Investigation Committee at the Yale University School of Medicine approved the study procedures and all participants signed an informed consent prior to study participation.

Guided Imagery Script Development and Training

During the session prior to the fMRI scan, six individually-tailored imagery scripts were developed from participants’ descriptions of 2 alcohol context cue, 2 stressful and 2 neutral-relaxing experiences using Scene Construction Questionnaires (Li, et al. 2005; Sinha 2009a), based on previously described standardized methods (Sinha 2009a). For stress scripts, participants identified, “a situation that made them sad, mad, upset and which in the moment they could do nothing to change it.” Examples of highly stressful situations include loss of a job, death of or conflict with a significant other and loss of an important relationship. As a manipulation check, the situations were rated by the participants on a 10-point Likert scale (1=not at all stressful and 10=the most stressful) and only those situations that were rated as 8 or above were found appropriate for stimulus provocation and used for script development. Alcohol context cue scripts were developed from individual experiences of alcohol anticipation and consumption (e.g., birthday celebration, meeting friends at a bar) and scenarios occurring in the context of negative affect or psychological distress were excluded. Specifically, the alcohol cue script was developed in response to the query, “please tell us about a recent situation when you really wanted an alcoholic drink and then you went ahead and had one.” Thus each subject provided their preferred individual situation of wanting and consuming an alcoholic beverage. Neutral scripts were based on the personal experiences of commonly experienced neutral-relaxing situations, such as laying on the beach or reading at the park. While individual stimulus and response content specific to an experience was included in each script, the script style, content format and length were standard across conditions and subjects, as described previously (Sinha 2009a). Each script was 2 minutes in length and was audio-taped in random order for presentation during the scanning session. During the scanning session, all research staff and fMRI technicians were blind to content, order and type of the script stimuli.

Efficacy of Script-driven Imagery Manipulation

The following procedures were implemented to ensure efficacy of the imagery manipulation. First, all participants completed the Questionnaire on Mental Imagery (Sheehan 1967) that measures individual difference in mental imagery ability, and individuals reporting average or above levels of imagery ability were included (Sinha 2009a). There were no statistical differences in scores of QMI between male (M=70.4, SD=20.2) and female (M=65.2, SD=22.3) participants. Additionally the scores of Toronto Alexithymia Scale (Bagby, et al. 1988) indicated that there were no statistical differences between men (M=58.1, SD=9.6) and women (M=58.6, SD=15.4), suggesting that men and women were equivalent in ability to reflect upon and rate their emotions.

Second, a structured relaxation and imagery training procedure, known to minimize variability in imagery ability (see (Sinha 2009a) for details), was implemented prior to the scanning session. Finally, each participant rated imagery vividness on a 10-point Likert scale (1=cannot visualize the image and 10=extremely clear, ‘as if’ it were happening right now) following each of the stress, alcohol cue and neutral trials, and there were no significant differences between men and women, or across conditions in vividness of the imagery for each trial (Men: M=8.2, SD=1.3, Women: M=8.8, SD=1.0).

The stress scripts were rated for the type of stress as either: Interpersonal (men: 72%, women: 72.5%; personal violation, relationship, betrayal), Environmental (men: 9 %, women: 2.5%; housing, legal, financial), Achievement (men: 17%, women: 22.5%; job, career), Medical (men: 2%, women: 2.5%; injury, illness). There were no differences in type of stressor by gender, χ2= 1.71, p = NS.

fMRI Acquisition

The 3-T Siemens Trio MRI system equipped with a single-channel, standard-quadrature head coil collected the images using T2*-sensitive gradient-recalled single shot echo-planar pulse sequence. Anatomical images were acquired with spin-echo imaging in the axial-plane parallel to the AC-PC line (repetition time (TR) = 300 msec, echo time (TE) = 2.5 msec, bandwidth = 300 Hz/pixel, flip angle = 60 degrees, field-of-view = 220×220 mm, matrix = 256×256, 32 slices, slice thickness = 4mm, no gap). Functional images were obtained using a single-shot gradient echo-planar imaging sequence with 32 axial slices parallel to the AC-PC line covering whole brain (TR = 2,000 msec, TE = 25 msec, bandwidth = 2004 Hz/pixel, flip angle = 85 degrees, field of view = 220×220 mm, matrix = 64×64, slice thickness = 4mm with no gap, 190 measurements). Once the functional images were collected, a high resolution 3D Magnetization Prepared Rapid Gradient-Echo sequence was used to acquire sagittal images for multi-subject registration. (TR = 2530 ms; TE = 3.34 ms; bandwidth = 180 Hz/pixel; flip angle = 7°; slice thickness = 1mm; field-of-view = 256 × 256 mm; matrix = 256 × 256).

fMRI Trials

A block design was used where each block comprised of a 5.5 minute (min) fMRI run that entailed a 1.5 min quiet baseline period followed by a 2.5 min imagery period (2 min of read-imagery and 0.5 min of quiet-imagery) and a 1-min quiet recovery period. During the baseline period, participants were asked to stay still in the scanner without engaging in any mental activity. During the recovery period, participants were instructed to stop imagining and lay still for another minute.

The order of all three script types were counterbalanced and randomized across subjects. Scripts from the same condition were never presented consecutively and each script was presented only once, such that different scripts were used per trial.

Behavioral Ratings Pre- and Post-Trials

Before and after each BOLD trial, participants were instructed to rate anxiety and craving levels using a 10-point verbal analog scale (VAS: 1=not at all, 10=extremely high). Anxiety rating refers to how “tense, anxious and/or jittery” they felt, and craving ratings indicate their “desire to drink alcohol at that moment”. To decrease and normalize any residual anxiety or craving from prior trials, participants engaged in a brief exposure of progressive relaxation between fMRI trials for 2 minutes. Participants were instructed to progressively relax muscles in each part of the body (e.g., arm, leg, stomach muscles). This technique is mainly focused on relaxing physiological muscle tension, and does not involve mental relaxation or imagery. After relaxation, anxiety and craving ratings returned back to baseline and there were no baseline differences across trials in these ratings.

fMRI Analysis

The raw imaging data was converted from Digital Imaging and Communication in Medicine format to Analyze format using XMedCon (Nolfe 2003). To achieve a steady-state equilibrium between radio-frequency pulsing and relaxation, the first ten images were discarded from the beginning of each functional run, leaving 180 measurements. Images were motion-corrected for three translational and three rotational directions (Friston, et al. 1996) discarding any trial with linear motion exceeding 1.5 mm or having a rotation greater than 2 degrees. At the individual level, General Linear Model (GLM) on each voxel in the entire brain volume was used with a regressor (time during imagery) for each trial per condition and the baseline for each trial was included separately as a regressor. The recovery period is excluded from the data analysis and was not used as the baseline regressor, due to the possibility of carryover effects from the imagery period. Each functional trial was spatially smoothed using a 6 mm Gaussian kernel and individually normalized to create beta-maps (3.44mm × 3.44mm × 4mm).

In order to adjust for individual anatomical differences, three registrations were sequentially conducted using the Yale BioImage Suite software package (Duncan, et al. 2004; Papademetris 2006); linear registration of raw data into 2D anatomical image, the 2D to 3D (1×1×1 mm) linear registration, a non-linear registration to a reference 3D image. The reference image was the Colin27 Brain (Holmes, et al. 1998) in Montreal Neurological Institute (MNI) space (Evans, et al. 1993).

The second level group analysis was conducted with Analysis of Functional NeuroImages software (Cox 1996) using random mixed effects models. A 2×3 ANOVA (sex by condition) was carried out with sex as the between-subject fixed-effect factor, condition (neutral/alcohol cues/stress) as the within-subject fixed-effect factor, and subject (N=43) as the random-effect factor. A FamilyWise Error rate (FWE) correction for multiple comparisons was applied using Monte Carlo simulations (Xiong, et al. 1995) conducted with AlphaSim in AFNI (Cox 1996) and set at p<.01 for the overall factorial analysis (Main effects and Interaction terms), and at p<.05 (FWE corrected) for simple effect analysis to understand source of the significant main effects and interactions.

Whole-brain correlation analyses with anxiety and alcohol craving were conducted using BioImage Suite (Papademetris 2006) with the application of AFNI AlphaSim FWE correction for multiple comparisons. To reduce the influence of any possible extreme values (outliers) in the correlation analyses, the Winsorization method (Chen and Dixon 1972; Dixon 1960) for values with a Cook’s Distance score greater than 1 was used. The correlation r value was presented after extreme values were reigned in to the value of the next highest score to reduce their influences. However, scatter plots (Figure 4) displayed all values without the Winsorization to show the overall patterns of the data.

Figure 4
Whole brain voxel-based correlation and corresponding scatter plots for (A) alcohol cue-induced craving ratings with neural responses in males as well as (B) stress-induced anxiety ratings with neural response in males and females (p<.05, whole-brain ...

Results

Demographics

Table 1 presents demographic characteristics and current levels of alcohol consumption in men and women. There were no significant differences in age, education and race by gender. As expected and consistent with general trends (Kessler, et al. 1994; Office for National Statistics 2006), women drank less than men on average, but there were no significant differences between genders in current levels of alcohol consumption.

Table 1
Demographic characteristics of men and women

Anxiety and Craving ratings

Condition and sex effects on self-report measures of craving and anxiety in each were assessed using linear mixed model with Condition (stress, alcohol, neutral) and Time-point (baseline, imagery) as within-subject factors and Sex as a between-subject factor (see Figure 1). Post-hoc t-tests were corrected for multiple comparisons using a modified Bonferroni procedure (Hochberg 1988).

Figure 1
Mean and standard error (SEM) in healthy men and women for verbal analog scales (VAS, 0-10) assessing (A) subjective anxiety and (B) alcohol craving ratings averaged across stress, alcohol cue and neutral relaxing imagery trials. (A) During stress imagery, ...

For the anxiety ratings, significant main effects of Condition (F(2 82)=26.6, p<.0001), Time-point (F(1 41) = 58.04, p<.0001) and a Condition X Time-point interaction (F(2, 80)=33.37, p<.0001) were observed. No other effects were significant including Sex main effect, Sex X Condition and Sex X Condition X Time-point interactions. There were no differences in anxiety ratings across the baseline period in each trial. However as expected, in the imagery period, anxiety during stress was greater than in the neutral (t=10.33, p<.0001) and in the alcohol (t=8.36, p<.001) conditions. When the imagery period was compared with the baseline period, anxiety ratings during imagery was significantly elevated from baseline only in the stress condition (t=10.98, p<.0001) and not in the neutral and alcohol cue conditions.

For the craving ratings, significant main effects of Condition (F(2 82)=4.24, p<.05), Time-point (F(1 41)=15.52, p<.001) and a Condition X Time-point (F(2 80)=10.3, p<0.0001) interaction were observed. No other effects were significant including Sex main effect, Sex X Condition and Sex X Condition X Time-point interactions. There were no differences in craving ratings across the baseline period in each trial. However, during the imagery period, craving in the alcohol-cue condition was greater than in the neutral (t=5.24, p<0.001) and stress (t=3.16, p<0.05) conditions. When the imagery period was compared with the baseline period, craving during imagery was greater than the baseline for the alcohol cue condition (t=5.59, p<.001) and not during the neutral and stress condition.

fMRI results

Main Effect of Condition: Brain activity during stress and alcohol cue conditions

A significant condition main effect (p<.01, whole-brain FWE corrected) on brain activation was observed for the medial and lateral OFC, ventromedial PFC, lateral PFC, superior/middle frontal gyrus (SFG/MFG), anterior and posterior cingulate cortex (ACC and PCC) and left anterior insula. Additionally activation in specific areas of superior/middle/inferior temporal lobe, superior/inferior parietal lobe, angular gyrus, occipital lobe and cerebellum were observed (see Figure 2). These regions were strongly activated for both Stress-Neutral and Alcohol cue-Neutral contrasts (see Table 2). Activations in the dorsal striatum were present only during stress exposure, while the ventral striatum, occipital lobe, bilateral MFG/precentral gyrus were evident only during the alcohol-cue exposure (see Table 2). Greater activity during alcohol-cue relative to stress were seen bilaterally in the pre-/post- central gyrus at p<0.01, whole-brain corrected (Left: t=2.81, 1592mm3, X=−52, Y=−6, Z=35; Right: t=2.97, 1967mm3, X=62, Y=−11, Z=25).

Figure 2
Whole brain voxel-based analyses showing (A) main effect of Condition, and (B) stress and (C) alcohol-cue induced increases in fMRI signal relative to neural responses in the neutral relaxing condition (p < 0.01, whole-brain FWE corrected). Selected ...
Table 2
Brain activations during stress and alcohol-cue exposures

Sex by Condition Interactions

A significant Sex X Condition interaction was evident in several regions of the cortico-striatal-limbic circuit (p<0.01, whole-brain FWE corrected) (see Table 3 and Figure 3). In the Stress-Neutral condition, men showed greater activations in brain regions involved in emotional modulation compared to women. These regions include the medial PFC (dorsomedial, ventromedial), rostral ACC, posterior insula, putamen, as well as limbic regions such as the amygdala, hippocampus, and parahippocampal gyrus. Additionally selected areas of superior/middle/inferior temporal lobe, superior parietal lobe, lingual gyrus and cerebellum were more activated in men compared to women. In the Alcohol cue-Neutral contrast, women displayed greater activation in the left superior/middle frontal gyrus (BA 6) compared with men (see Table 3, Figure 3).

Figure 3
Whole brain voxel-based fMRI images showing Sex X Condition interaction and corresponding activations in the Stress-Neutral and Alcohol Cue-Neutral contrasts for males (M) and females (F). (A) Sex X Condition interaction effects were significant in regions ...
Table 3
Sex differences in brain activations during stress and alcohol-cue exposures.

Secondary analyses including days of alcohol used per week (frequency) and amount of current alcohol use as covariates were also conducted and the above results were unchanged.

Correlational Analysis

For stress-induced anxiety, whole brain correlation analysis revealed differential associations for men and women (p<0.05, whole-brain FWE corrected). In men, significant positive correlations with anxiety were observed in the medial OFC, ventromedial PFC, left superior-medial PFC and rostral ACC. In women, stress-induced anxiety was significantly associated with brain activity in the middle and superior frontal regions (see Table 4 and Figure 4). There were no outliers in the relation between brain activity and stress-induced anxiety in men. In women, there was one extreme value (greater than 1 using Cook’s distance) in the relationship between female anxiety and SFG/MFG activity. The correlation was still significant even after removing this value. To reduce the influence of this value, the r value was presented after the Winsorization in Table 4 (r=.62).

Table 4
Neural correlates of alcohol cue-induced craving and stress-induced anxiety

For alcohol cue-induced craving, male alcohol craving was positively associated with activity in the striatum, right dorsolateral and lateral PFC, ACC, and middle/inferior temporal lobe (p<0.05, whole-brain corrected; see Table 4 and Figure 4). The striatum cluster encompassing both the ventral and dorsal portion was significantly positively correlated with alcohol craving (Figure 4). No outlier scores were present in associations between craving and the striatum as well as other brain regions (Table 4). There were no brain regions associated with female alcohol craving that survived multiple comparisons.

Discussion

The current findings indicate overlapping neural responses to stress and alcohol context cues in healthy individuals with increased activation of the corticostriatal-limbic circuit encompassing the medial and lateral PFC, ACC, PCC, anterior insula, and striatum, areas known to be involved in processing of emotions, stress and rewarding stimuli. Furthermore, significant sex differences in neural processing of stress and alcohol context cues were observed, suggesting sex-specific functional responses to stress and alcohol cues. These differences in neural responses likely contribute to the well known sex differences in stress-related coping and in vulnerabilities to stress-related psychiatric disorders.

During stress and alcohol-cue exposure, strong medial and lateral prefrontal activation along with increased activity in ACC was evident. The PFC is involved in executive control and emotion regulation (Ochsner, et al. 2004), and the ACC is associated with online conflict monitoring (MacDonald, et al. 2000). Both these regions were active during stress and alcohol-cue exposures, indicating activation of neuroregulatory systems for on-line modulation of stress and alcohol cue experiences. Furthermore, the anterior insula was activated, which is known to be involved in interoceptive processing of emotion, pain and reward (Harris, et al. 2009; Hollander, et al. 2008). Ventral striatum activation was seen during alcohol-cue exposure, while the right dorsal striatum increased during stress exposure. Increases in dorsal striatal activity during stress have been reported previously (Sinha and Li 2007) and chronic stress is known to alter dorsal striatal projections to the frontal cortex (Rossi, et al. 2009), supporting the notion that stress influences habit-based decision making involving fronto-striatal pathways (Dias-Ferreira, et al. 2009). The ventral striatum (VS) has been associated with reward processing (Haber and Knutson 2010), and our findings of specific activation in the ventral striatum during alcohol context cue exposure is consistent with this observation and previous studies showing VS activation with an alcohol taste cue (Filbey, et al. 2008) and intravenous injection of alcohol (Gilman, et al. 2008).

In comparing the alcohol cue with the stress condition, greater activity in the premotor region was seen in the alcohol cue relative to the stress condition, suggesting that action-specific components of emotion may be more activated during this condition. This is consistent with previous research indicating that pleasant emotions facilitate approach-related behaviors and psychomotor activation, whereas unpleasant and stressful emotion promotes defensive urges (Lang 2000; Lang, et al. 1997). Alcohol is also shown to generate positive appetitive states in healthy social drinkers (Lukas, et al. 1986) and it is suggested that motor control is an essential part of appetitive processing (Haber and Knutson 2010).

Sex differences in neural responses were also observed. During stress, men showed greater activation in brain regions including the ventromedial PFC, rostral ACC, posterior insula, amygdala and hippocampus than women. The neural circuit connecting the medial PFC, rostral ACC, and amygdala is regarded as the core circuit for emotional modulation (Davidson, et al. 2000; Ochsner, et al. 2004), especially stress experiences (Li and Sinha 2008; Sinha, et al. 2006). Male-specific hyperactivity in emotion-related brain regions are consistent with prior research indicating greater emotional and physiological responses in men following stress compared to women, including higher cortisol levels (Kudielka and Kirschbaum 2005) and diastolic blood pressure responses (Chaplin, et al. 2008) and greater negative and aggressive emotions (Verona, et al. 2007). Greater sensitivity to stress-related conditioning effects has also been reported in males relative to females in animal (Wood, et al. 2001; Wood and Shors 1998) and in human studies (Jackson, et al. 2006). In contrast, females showed greater activity in the SFG and MFG during alcohol-cue exposures. The SFG/MFG is involved in high-level cognitive processing such as reasoning (Goel and Dolan 2003), working memory (Smith and Jonides 1999) and attention during language processing (Cabeza and Nyberg 2000). Greater activations in these regions during alcohol cues reflect that healthy women may utilize attention and language-based processing of alcohol context cues. Interestingly, these sex differences in neural responses to stress and alcohol cues are consistent with previous psychobiological and learning studies indicating a tendency in males towards utilizing interoceptive and associative cues to identify emotions and in learning tasks, while females utilizing external, context-dependent stimuli to identify their emotions and in learning tasks (Herman and Wallen 2007; Roberts and Pennebaker 1995; Sandstrom 2007; Sandstrom, et al. 1998). Thus, males and females appear to rely on different types of information in emotion, stress and learning contexts, which in turn, are likely to activate different brain regions in a sex-specific manner, as observed in the current data.

Sex-specific patterns were also evident in the relationship between brain activity and stress-induced anxiety ratings. In men, stress-induced anxiety was positively correlated with activity in the ventromedial PFC, medial OFC, left superior-medial PFC and ACC, areas showing greater stress-related activation in men. Associations with these emotion modulatory regions (Davidson, et al. 2000; Ochsner, et al. 2004) suggest more emotion-focused processing in males while experiencing stress-induced anxiety. In females, SFG/MFG activity was positively correlated with stress-induced anxiety. The SFG/MFG are involved in cognitive processing (Cabeza and Nyberg 2000; Goel and Dolan 2003) and also closely interact with anterior parts of PFC to guide emotional behaviors (Koechlin, et al. 2000). Recent evidence indicates that the SFG/MFG contributes to response correction during reasoning processes (Kalbfleisch, et al. 2007), and activity in these regions increased in individuals with anxious tendencies (Karch, et al. 2008). These findings suggest greater utilization of cognitive processes in experiencing stress-induced anxiety in women.

For alcohol-cue induced craving, significant neural correlates of male craving were found dominantly in the striatum and also selected regions of right dorsolateral/lateral PFC, ACC and middle/inferior temporal lobe. The association of striatal activity with craving is consistent with previous studies with alcohol-dependent individuals (Heinz, et al. 2004; Modell and Mountz 1995; Myrick, et al. 2004) as well as other addictive disorders (Rothemund, et al. 2007; Vanderschuren, et al. 2005; Volkow, et al. 2006). We found significant correlations between craving and brain activity in both ventral and dorsal striatum. In reinforcement learning, the ventral striatum is thought to be engaged in learning reward values, and the dorsal striatum maintains reward values to guide decision and behaviors (Kahnt, et al. 2009). Studies showed that the dorsal striatum is specifically involved in action initiation and in habit learning, including chronic drug use habits (Kahnt, et al. 2009; Porrino, et al. 2004; Volkow, et al. 2006). It is also known that the dorsal striatum is associated with craving when conditioned stimuli (e.g, cues) are presented to human subjects (Volkow, et al. 2006). Concurrent correlated activity of the ventral and dorsal striatum with craving in our data suggests that desire for alcohol involves processing and actively pursuing reward values in the presence of alcohol context cues. It is notable that we found this association in healthy men, since previous studies have shown correlations between striatal activity and craving in individuals with addictive disorders or in heavy drinkers, but not in healthy individuals. This suggests the involvement of the striatum in motivational aspects of wanting in both healthy and in clinical samples.

In addition, the correlation with alcohol craving was found in neural circuit of reward regulation, connecting DLPFC, ACC and the striatum. The DLPFC and ACC are regarded as key regulatory regions for reward processing, with the dorsal ACC showing an involvement in monitoring reward and the DLPFC evaluating these stimuli for reward-based decision-making (Haber and Knutson 2010). The DLPFC is also involved in context-dependent processing associated with drug/reward cues (Wilson, et al. 2004). Individuals having alcohol use disorder showed increased activity in DLPFC (George, et al. 2001) compared to healthy social drinkers. Research suggests that altered functional connectivity between DLPFC and striatum significantly contributes to increased craving in individuals with alcohol dependence (Park, et al. 2010). Further, increased activity in the ACC and striatum was associated with high levels of alcohol craving in alcoholic participants (Myrick, et al. 2004). These results, along with our finding, suggests that the neural circuit connecting the striatum, ACC, and DLPFC plays an important role in the modulation of alcohol-cue induced motivation.

Unlike in men, we did not find significant association of brain activity with alcohol craving that survived whole-brain correction in women. This result is similar to previous studies showing alcohol-cue induced craving only in men, but not in healthy socially drinking women (Willner, et al. 1998). As alcohol craving is known to be influenced by hormonal and mood fluctuations (Epstein, et al. 2006; Kraus, et al. 2004; Rubonis, et al. 1994) in women, it is possible that these factors affected the lack of strong neural associations with craving in women. Furthermore, women were drinking at lower levels than men, albeit not significantly less so, and hence recruitment of women with moderate to heavy drinking habits in future studies would be important to identify neural correlates of alcohol craving in women.

Conclusion

Taken together, the current findings provide important neural insights into sex differences in stress-related coping and alcohol-related behaviors. Previous research indicates that men show more automatic and behaviorally-oriented emotional expression and instrumental coping responses, whereas women tend to verbally express their emotion and utilize verbal coping strategies (Barrett, et al. 2000; Brody 1993). Further, women are more likely to engage in conversation, prayer and rumination (Nolen-Hoeksema, et al. 1999; Tamres, et al. 2002) following stress consistent with current data showing engagement of cognitive and verbal brain regions in female stress-induced anxiety. Men’s tendencies of instrumental and action-oriented stress coping, such as smoking and drinking (Lindquist, et al. 1997; Tamres, et al. 2002), are consistent with current data on significant association between striatal activity and alcohol craving as well as greater reactivity in the emotion-action brain regions during stress. It further supports research showing greater male-specific vulnerability for developing alcohol use disorders (Kessler, et al. 1994) and greater female-specific vulnerability to rumination and mood disorders (Kessler, et al. 1993). Thus, the current data on sex-specific neural response to stress and alcohol context cues provide novel insights for understanding sex differences in stress-related vulnerabilities in the development of stress related disorders such as depression and alcohol use disorders.

ACKNOWLEDGEMENTS

This research was supported by grants from the NIH Roadmap for Medical Research Common Fund, its Office of Research on Women’s Health and the National Institutes of Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism (NIAAA): UL1-DE019586 (RS), P50-DA016556 (RS), R01-AA13892 (RS), PL1-DA024859 (RS), and RL5-DA024858 (PI: Carolyn Mazure). We also thank Adam K. Hong for his technical assistance for this study.

Footnotes

FINANCIAL DISCLOSURES: All authors do not have direct or indirect financial or personal relationships, interests, and affiliations relevant to the subject matter of the manuscript that have occurred over the last two years, nor that are expected in the foreseeable future. Dr. Sinha is on the Scientific Advisory Board for Embera Neurotherapeutics and is also a consultant for Glaxo-Smith Kline, Pharmaceuticals.

References

  • Bagby RM, Taylor GJ, Parker JD. Construct validity of the Toronto Alexithymia Scale. Psychother Psychosom. 1988;50(1):29–34. [PubMed]
  • Barrett L, Lane R, Sechrest L, Schwartz G. Sex Differences in Emotional Awareness. Personality and Social Psychology Bullentin. 2000;26:1027–1035.
  • Becker JB, Monteggia LM, Perrot-Sinal TS, Romeo RD, Taylor JR, Yehuda R, Bale TL. Stress and disease: is being female a predisposing factor? J Neurosci. 2007;27(44):11851–5. [PubMed]
  • Boscarino JA, Adams RE, Galea S. Alcohol use in New York after the terrorist attacks: a study of the effects of psychological trauma on drinking behavior. Addict Behav. 2006;31(4):606–21. [PMC free article] [PubMed]
  • Brody LR, Hall JA. Gender and Emotion. Handbook of Emotions. 1993:14.
  • Cabeza R, Nyberg L. Imaging cognition II: An empirical review of 275 PET and fMRI studies. J Cogn Neurosci. 2000;12(1):1–47. [PubMed]
  • Cacioppo JT, Gardner WL, Berntson GG. The affect system has parallel and integrative processing components: Form follows function. Journal of Personality and Social Psychology. 1999;76:839–855.
  • Carver CS. Affect and the functional bases of behavior: On the dimensional structure of affective experience. Personality and Social Psychology Review. 2001;5:345–356.
  • Chaplin TM, Hong K, Bergquist K, Sinha R. Gender differences in response to emotional stress: an assessment across subjective, behavioral, and physiological domains and relations to alcohol craving. Alcohol Clin Exp Res. 2008;32(7):1242–50. [PMC free article] [PubMed]
  • Chen EH, Dixon WJ. Estimates of Parameters of a Censored Regression Sample. Journal of the American Statistical Association. 1972;67(339):664–671.
  • Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA. 2007;298(14):1685–7. [PubMed]
  • Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res. 1996;29(3):162–73. [PubMed]
  • Davidson RJ, Putnam KM, Larson CL. Dysfunction in the neural circuitry of emotion regulation--a possible prelude to violence. Science. 2000;289(5479):591–4. [PubMed]
  • Dawson DA, Grant BF, Ruan WJ. The Association Between Stress and Drinking: Modifying Effects of Gender and Vulnerability. Alcohol and Alcoholism. 2005;40(5):453–460. [PubMed]
  • Dias-Ferreira E, Sousa JC, Melo I, Morgado P, Mesquita AR, Cerqueira JJ, Costa RM, Sousa N. Chronic stress causes frontostriatal reorganization and affects decision-making. Science. 2009;325(5940):621–5. [PubMed]
  • Dixon WJ. Simplified Estimation from Censored Normal Samples. Annals of Mathematical Statistics. 1960;31(2):385–391.
  • Duncan JS, Papademetris X, Yang J, Jackowski M, Zeng X, Staib LH. Geometric strategies for neuroanatomic analysis from MRI. Neuroimage. 2004;23(Suppl 1):S34–45. [PMC free article] [PubMed]
  • Epstein EE, Rhines KC, Cook S, Zdep-Mattocks B, Jensen NK, Mccrady BS. Changes in alcohol craving and consumption by phase of menstrual cycle in alcohol dependent women. Journal of Substance Use. 2006;11(5):323–332.
  • Evans A, Collins D, Mills S, Brown E, Kelly R, Peters T. 3D statistical neuroanatomical models from 305 MRI volumes. Nuclear Science Symposium and Medical Imaging Conference; San Francisco, CA, USA. 1993. pp. 1813–1817.
  • Filbey FM, Claus E, Audette AR, Niculescu M, Banich MT, Tanabe J, Du YP, Hutchison KE. Exposure to the taste of alcohol elicits activation of the mesocorticolimbic neurocircuitry. Neuropsychopharmacology. 2008;33(6):1391–401. [PMC free article] [PubMed]
  • Fox HC, Hong KI, Siedlarz K, Sinha R. Enhanced sensitivity to stress and drug/alcohol craving in abstinent cocaine-dependent individuals compared to social drinkers. Neuropsychopharmacology. 2008;33(4):796–805. [PMC free article] [PubMed]
  • Friston KJ, Williams S, Howard R, Frackowiak RS, Turner R. Movement-related effects in fMRI time-series. Magn Reson Med. 1996;35(3):346–55. [PubMed]
  • Garavan H, Pendergrass JC, Ross TJ, Stein EA, Risinger RC. Amygdala response to both positively and negatively valenced stimuli. Neuroreport. 2001;12(12):2779–83. [PubMed]
  • George MS, Anton RF, Bloomer C, Teneback C, Drobes DJ, Lorberbaum JP, Nahas Z, Vincent DJ. Activation of prefrontal cortex and anterior thalamus in alcoholic subjects on exposure to alcohol-specific cues. Arch Gen Psychiatry. 2001;58(4):345–52. [PubMed]
  • Gilman JM, Ramchandani VA, Davis MB, Bjork JM, Hommer DW. Why we like to drink: a functional magnetic resonance imaging study of the rewarding and anxiolytic effects of alcohol. J Neurosci. 2008;28(18):4583–91. [PMC free article] [PubMed]
  • Goel V, Dolan RJ. Reciprocal neural response within lateral and ventral medial prefrontal cortex during hot and cold reasoning. Neuroimage. 2003;20(4):2314–21. [PubMed]
  • Goldstein JM, Jerram M, Abbs B, Whitfield-Gabrieli S, Makris N. Sex differences in stress response circuitry activation dependent on female hormonal cycle. J Neurosci. 2010;30(2):431–8. [PMC free article] [PubMed]
  • Grzywacz JG, Almeida DM. Stress and Binge Drinking: A Daily Process Examination of Stressor Pile-up and Socioeconomic Status in Affect Regulation. Int J Stress Manag. 2008;15(4):364–380. [PMC free article] [PubMed]
  • Haber SN, Knutson B. The Reward Circuit: Linking Primate Anatomy and Human Imaging. Neuropsychopharmacology. 2010 [PMC free article] [PubMed]
  • Harris RE, Sundgren PC, Craig AD, Kirshenbaum E, Sen A, Napadow V, Clauw DJ. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum. 2009;60(10):3146–52. [PMC free article] [PubMed]
  • Heinz A, Siessmeier T, Wrase J, Hermann D, Klein S, Grusser SM, Flor H, Braus DF, Buchholz HG, Grunder G, Schreckenberger M, Smolka MN, Rosch F, Mann K, Bartenstein P. Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving. Am J Psychiatry. 2004;161(10):1783–9. [PubMed]
  • Herman RA, Wallen K. Cognitive performance in rhesus monkeys varies by sex and prenatal androgen exposure. Horm Behav. 2007;51(4):496–507. [PMC free article] [PubMed]
  • Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1988;75(4):800–2.
  • Hollander JA, Lu Q, Cameron MD, Kamenecka TM, Kenny PJ. Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci U S A. 2008;105(49):19480–5. [PubMed]
  • Holmes CJ, Hoge R, Collins L, Woods R, Toga AW, Evans AC. Enhancement of MR images using registration for signal averaging. J Comput Assist Tomogr. 1998;22(2):324–33. [PubMed]
  • Jackson ED, Payne JD, Nadel L, Jacobs WJ. Stress differentially modulates fear conditioning in healthy men and women. Biol Psychiatry. 2006;59(6):516–22. [PubMed]
  • Kahnt T, Park SQ, Cohen MX, Beck A, Heinz A, Wrase J. Dorsal striatal-midbrain connectivity in humans predicts how reinforcements are used to guide decisions. J Cogn Neurosci. 2009;21(7):1332–45. [PubMed]
  • Kalbfleisch ML, Van Meter JW, Zeffiro TA. The influences of task difficulty and response correctness on neural systems supporting fluid reasoning. Cogn Neurodyn. 2007;1(1):71–84. [PMC free article] [PubMed]
  • Karch S, Jager L, Karamatskos E, Graz C, Stammel A, Flatz W, Lutz J, Holtschmidt-Taschner B, Genius J, Leicht G, Pogarell O, Born C, Moller HJ, Hegerl U, Reiser M, Soyka M, Mulert C. Influence of trait anxiety on inhibitory control in alcohol-dependent patients: simultaneous acquisition of ERPs and BOLD responses. J Psychiatr Res. 2008;42(9):734–45. [PubMed]
  • Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29(2-3):85–96. [PubMed]
  • Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(1):8–19. [PubMed]
  • Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH. Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom Med. 1999;61(2):154–62. [PubMed]
  • Koechlin E, Corrado G, Pietrini P, Grafman J. Dissociating the role of the medial and lateral anterior prefrontal cortex in human planning. Proc Natl Acad Sci U S A. 2000;97(13):7651–6. [PubMed]
  • Kraus T, Reulbach U, Bayerlein K, Mugele B, Hillemacher T, Sperling W, Kornhuber J, Bleich S. Leptin is associated with craving in females with alcoholism. Addict Biol. 2004;9(3-4):213–9. [PubMed]
  • Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol. 2005;69(1):113–32. [PubMed]
  • Lang PJ. Emotion and motivation: Attention, perception, and action. Journal of Sport and Exercise Psychology. 2000;(22):S122–S140.
  • Lang PJ, Bradley MM, Cuthbert MM. Motivated attention: Affect, activation and action. Lawrence Erlbaum Associates, Inc.; Hillsdale, NJ: 1997. p. 39.
  • Li CS, Kosten TR, Sinha R. Sex differences in brain activation during stress imagery in abstinent cocaine users: a functional magnetic resonance imaging study. Biol Psychiatry. 2005;57(5):487–94. [PubMed]
  • Li CS, Sinha R. Inhibitory control and emotional stress regulation: neuroimaging evidence for frontal-limbic dysfunction in psycho-stimulant addiction. Neurosci Biobehav Rev. 2008;32(3):581–97. [PMC free article] [PubMed]
  • Lindquist TL, Beilin LJ, Knuiman MW. Influence of lifestyle, coping, and job stress on blood pressure in men and women. Hypertension. 1997;29(1 Pt 1):1–7. [PubMed]
  • Lopez JF, Akil H, Watson SJ. Neural circuits mediating stress. Biol Psychiatry. 1999;46(11):1461–71. [PubMed]
  • Lukas SE, Mendelson JH, Benedikt RA, Jones B. EEG alpha activity increases during transient episodes of ethanol-induced euphoria. Pharmacol Biochem Behav. 1986;25(4):889–95. [PubMed]
  • MacDonald AW, 3rd, Cohen JD, Stenger VA, Carter CS. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science. 2000;288(5472):1835–8. [PubMed]
  • Modell JG, Mountz JM. Focal cerebral blood flow change during craving for alcohol measured by SPECT. J Neuropsychiatry Clin Neurosci. 1995;7(1):15–22. [PubMed]
  • Myrick H, Anton RF, Li X, Henderson S, Drobes D, Voronin K, George MS. Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving. Neuropsychopharmacology. 2004;29(2):393–402. [PubMed]
  • Nachmias M, Gunnar M, Mangelsdorf S, Parritz RH, Buss K. Behavioral inhibition and stress reactivity: the moderating role of attachment security. Child Dev. 1996;67(2):508–22. [PubMed]
  • Nolen-Hoeksema S. Sex differences in unipolar depression: Evidence and theory. Psychological Bulletin. 1987;101(2):259–282. [PubMed]
  • Nolen-Hoeksema S, Larson J, Grayson C. Explaining the gender difference in depressive symptoms. J Pers Soc Psychol. 1999;77(5):1061–72. [PubMed]
  • Nolfe E. XMedCon- An open-source medical image conversion toolkit. European journal of nuclear medicine. 2003;30(Supp.2)
  • Ochsner KN, Ray RD, Cooper JC, Robertson ER, Chopra S, Gabrieli JD, Gross JJ. For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion. Neuroimage. 2004;23(2):483–99. [PubMed]
  • Office for National Statistics Smoking and drinking among adults. General Household Survey 2005. 2006 http://www.statistics.gov.uk/ghs.
  • Papademetris X. BioImage Suite: An Intergrated medical image analysis suite [database on the Internet] Section of Bioimaging Sciences, Deptartment of Diagnostic Radiology, Yale School of Medicine; New Haven: 2006. http://bioimagesuite.org.
  • Park SQ, Kahnt T, Beck A, Cohen MX, Dolan RJ, Wrase J, Heinz A. Prefrontal cortex fails to learn from reward prediction errors in alcohol dependence. J Neurosci. 2010;30(22):7749–53. [PMC free article] [PubMed]
  • Porrino LJ, Lyons D, Smith HR, Daunais JB, Nader MA. Cocaine self-administration produces a progressive involvement of limbic, association, and sensorimotor striatal domains. J Neurosci. 2004;24(14):3554–62. [PubMed]
  • Roberts TA, Pennebaker JW. Women’s and men’s strategies in perceiving internal state. In: Zanna IM, editor. Advances in experimental social psychology. Academic Press; New York: 1995. pp. 143–176.
  • Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev. 1993;18(3):247–91. [PubMed]
  • Rossi S, De Chiara V, Musella A, Mataluni G, Sacchetti L, Bernardi G, Usiello A, Centonze D. Adaptations of striatal endocannabinoid system during stress. Mol Neurobiol. 2009;39(3):178–84. [PubMed]
  • Rothemund Y, Preuschhof C, Bohner G, Bauknecht HC, Klingebiel R, Flor H, Klapp BF. Differential activation of the dorsal striatum by high-calorie visual food stimuli in obese individuals. Neuroimage. 2007;37(2):410–21. [PubMed]
  • Rubonis AV, Colby SM, Monti PM, Rohsenow DJ, Gulliver SB, Sirota AD. Alcohol cue reactivity and mood induction in male and female alcoholics. J Stud Alcohol. 1994;55(4):487–94. [PubMed]
  • Sandstrom NJ. Sex differences in use of visual cues by rhesus monkeys performing a spatial learning task: comment on “Cognitive performance in rhesus monkeys varies by sex and prenatal androgen exposure” by Herman and Wallen. Horm Behav. 2007;52(2):139–42. [PubMed]
  • Sandstrom NJ, Kaufman J, Huettel SA. Males and females use different distal cues in a virtual environment navigation task. Brain Res Cogn Brain Res. 1998;6(4):351–60. [PubMed]
  • Schneider F, Habel U, Wagner M, Franke P, Salloum JB, Shah NJ, Toni I, Sulzbach C, Honig K, Maier W, Gaebel W, Zilles K. Subcortical correlates of craving in recently abstinent alcoholic patients. Am J Psychiatry. 2001;158(7):1075–83. [PubMed]
  • Schott BH, Minuzzi L, Krebs RM, Elmenhorst D, Lang M, Winz OH, Seidenbecher CI, Coenen HH, Heinze HJ, Zilles K, Duzel E, Bauer A. Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release. J Neurosci. 2008;28(52):14311–9. [PubMed]
  • Sheehan P. A shortened version of the Bett’s questionnaire upon mental imagery. Journal of Clinical Psychology. 1967;23:386–389. [PubMed]
  • Sinha R. Modeling stress and drug craving in the laboratory: implications for addiction treatment development. Addict Biol. 2009a;14(1):84–98. [PMC free article] [PubMed]
  • Sinha R. Stress and addiction: a dynamic interplay of genes, environment, and drug intake. Biol Psychiatry. 2009b;66(2):100–1. [PMC free article] [PubMed]
  • Sinha R, Fox HC, Hong KA, Bergquist K, Bhagwagar Z, Siedlarz KM. Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals. Neuropsychopharmacology. 2009;34(5):1198–208. [PMC free article] [PubMed]
  • Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ. Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatry. 2006;63(3):324–31. [PubMed]
  • Sinha R, Lacadie C, Skudlarski P, Wexler BE. Neural circuits underlying emotional distress in humans. Ann N Y Acad Sci. 2004;1032:254–7. [PubMed]
  • Sinha R, Li CS. Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug Alcohol Rev. 2007;26(1):25–31. [PubMed]
  • Smith EE, Jonides J. Storage and executive processes in the frontal lobes. Science. 1999;283(5408):1657–61. [PubMed]
  • Tamres LK, Janicki D, Helgeson VS. Sex differences in coping behavior: A meta-analytic review and an examination of relative coping. Personality and Social Psychology Review. 2002;(6):2–30.
  • Vanderschuren LJ, Di Ciano P, Everitt BJ. Involvement of the dorsal striatum in cue-controlled cocaine seeking. J Neurosci. 2005;25(38):8665–70. [PubMed]
  • Verona E, Reed A, 2nd, Curtin JJ, Pole M. Gender differences in emotional and overt/covert aggressive responses to stress. Aggress Behav. 2007;33(3):261–71. [PubMed]
  • Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, Jayne M, Ma Y, Wong C. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006;26(24):6583–8. [PubMed]
  • Willner P, Field M, Pitts K, Reeve G. Mood, cue and gender influences on motivation, craving and liking for alcohol in recreational drinkers. Behav Pharmacol. 1998;9(7):631–42. [PubMed]
  • Wilson SJ, Sayette MA, Fiez JA. Prefrontal responses to drug cues: a neurocognitive analysis. Nat Neurosci. 2004;7(3):211–4. [PMC free article] [PubMed]
  • Wood GE, Beylin AV, Shors TJ. The contribution of adrenal and reproductive hormones to the opposing effects of stress on trace conditioning in males versus females. Behav Neurosci. 2001;115(1):175–87. [PubMed]
  • Wood GE, Shors TJ. Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones. Proc Natl Acad Sci U S A. 1998;95(7):4066–71. [PubMed]
  • Wrase J, Schlagenhauf F, Kienast T, Wustenberg T, Bermpohl F, Kahnt T, Beck A, Strohle A, Juckel G, Knutson B, Heinz A. Dysfunction of reward processing correlates with alcohol craving in detoxified alcoholics. Neuroimage. 2007;35(2):787–94. [PubMed]
  • Xiong J, Gao J-H, Lancaster JL, Fox PT. Clustered pixels analysis for functional MRI activation studies of the human brain. Human Brain Mapping. 1995;3:287–301.
  • Zhou Z, Zhu G, Hariri AR, Enoch MA, Scott D, Sinha R, Virkkunen M, Mash DC, Lipsky RH, Hu XZ, Hodgkinson CA, Xu K, Buzas B, Yuan Q, Shen PH, Ferrell RE, Manuck SB, Brown SM, Hauger RL, Stohler CS, Zubieta JK, Goldman D. Genetic variation in human NPY expression affects stress response and emotion. Nature. 2008;452(7190):997–1001. [PMC free article] [PubMed]