White matter microstructure differences in individuals with dependence on cocaine, methamphetamine, and nicotine: Findings from the ENIGMA-Addiction working group.

BACKGROUND: Nicotine and illicit stimulants are very addictive substances. Although associations between grey matter and dependence on stimulants have been frequently reported, white matter correlates have received less attention. METHODS: Eleven international sites ascribed to the ENIGMA-Addiction consortium contributed data from individuals with dependence on cocaine (n = 147), methamphetamine (n = 132) and nicotine (n = 189), as well as non-dependent controls (n = 333). We compared the fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) of 20 bilateral tracts. Also, we compared the performance of various machine learning algorithms in deriving brain-based classifications on stimulant dependence. RESULTS: The cocaine and methamphetamine groups had lower regional FA and higher RD in several association, commissural, and projection white matter tracts. The methamphetamine dependent group additionally showed lower regional AD. The nicotine group had lower FA and higher RD limited to the anterior limb of the internal capsule. The best performing machine learning algorithm was the support vector machine (SVM). The SVM successfully classified individuals with dependence on cocaine (AUC = 0.70, p < 0.001) and methamphetamine (AUC = 0.71, p < 0.001) relative to non-dependent controls. Classifications related to nicotine dependence proved modest (AUC = 0.62, p = 0.014). CONCLUSIONS: Stimulant dependence was related to FA disturbances within tracts consistent with a role in addiction. The multivariate pattern of white matter differences proved sufficient to identify individuals with stimulant dependence, particularly for cocaine and methamphetamine.

Associations between depression, lifestyle and brain structure: A longitudinal MRI study.

BACKGROUND: Depression has been associated with decreased regional grey matter volume, which might partly be explained by an unhealthier lifestyle in depressed individuals which has been ignored by most earlier studies. Also, the longitudinal nature of depression, lifestyle and brain structure associations is largely unknown. This study investigates the relationship of depression and lifestyle with brain structure cross-sectionally and longitudinally over up to 9 years. METHODS: We used longitudinal structural MRI data of persons with depression and/or anxiety disorders and controls (Nunique participants = 347, Nobservations = 609). Cortical thickness of medial orbitofrontal cortex (mOFC), rostral anterior cingulate cortex (rACC) and hippocampal volume were derived using FreeSurfer. Using Generalized Estimating Equations, we investigated associations of depression and lifestyle (Body mass index (BMI), smoking, alcohol consumption, physical activity and sleep duration) with brain structure and change in brain structure over 2 (n = 179) and 9 years (n = 82). RESULTS: Depression status (B = -.053, p = .002) and severity (B = -.002, p = .002) were negatively associated with rACC thickness. mOFC thickness was negatively associated with BMI (B = -.004, p < .001) and positively with moderate alcohol consumption (B = .030, p = .009). All associations were independent of each other. No associations were observed between (change in) depression, disease burden or lifestyle factors with brain change over time. CONCLUSIONS: Depressive symptoms and diagnosis were independently associated with thinner rACC, BMI with thinner mOFC, and moderate alcohol consumption with thicker mOFC. No longitudinal associations were observed, suggesting that regional grey matter alterations are a long-term consequence or vulnerability indicator for depression but not dynamically or progressively related to depression course trajectory.

Mapping cortical and subcortical asymmetries in substance dependence: Findings from the ENIGMA Addiction Working Group.

Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.

Cerebral effects of glucagon-like peptide-1 receptor blockade before and after Roux-en-Y gastric bypass surgery in obese women: A proof-of-concept resting-state functional MRI study.

AIM: To assess the effects of Roux-en-Y gastric bypass surgery (RYGB)-related changes in glucagon-like peptide-1 (GLP-1) on cerebral resting-state functioning in obese women. MATERIALS AND METHODS: In nine obese females aged 40-54 years in the fasted state, we studied the effects of RYGB and GLP-1 on five a priori selected networks implicated in food- and reward-related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks). RESULTS: Before surgery, GLP-1 receptor blockade (using exendin9-39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP-1 receptor blockade had a larger effect on connectivity in this region than GLP-1 receptor blockade before RYGB (all PFWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB. CONCLUSIONS: These findings suggest GLP-1 involvement in resting-state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP-1-induced changes in resting-state connectivity in RYGB-mediated weight loss and appetite control.

Subcortical surface morphometry in substance dependence: An ENIGMA addiction working group study.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

Changes in brain white matter integrity after systemic treatment for breast cancer: a prospective longitudinal study.

An increasing number of studies suggest chemotherapy for breast cancer may be neurotoxic. Cross-sectional MRI diffusion tensor imaging (DTI) studies suggest a vulnerability of brain white matter to various chemotherapeutic regimens. Up till now, this was confirmed in one prospective DTI study: Deprez et al. (2012) showed a widespread decline in fractional anisotropy (FA) of breast cancer patients after chemotherapy consisting of 5-fluorouracil (5-FU), epirubicin and cyclophosphamide (FEC) +/- taxanes +/- endocrine treatment. Our aim was to evaluate whether similar detrimental effects on white matter integrity would be observed with the currently widely prescribed anthracycline-based chemotherapy for breast cancer (predominantly doxorubicin and cyclophosphamide +/- taxanes +/- endocrine treatment (=BC + SYST; n = 26) compared to no systemic treatment (BC; n = 23) and no-cancer controls (NC; n = 30). Assessment took place before and six months after chemotherapy, and matched intervals for the unexposed groups. DTI data were analyzed using voxel-based tract-based spatial statistics and region of interest (ROI) analysis. Voxel-based analysis did not show an effect of chemotherapy +/- endocrine treatment on white matter integrity. ROI analysis however indicated subtle detrimental effects of chemotherapy +/- endocrine treatment by showing a larger decline in WM integrity in the superior longitudinal fasciculus and corticospinal tract in BC + SYST than BC. Indications for relatively mild neurotoxicity in our study might be explained by patient characteristics and specific aspects of data analysis. The omission of 5-FU in current treatment regimens or the administration of doxorubicin instead of epirubicin is also discussed as an explanation for the observed effects.

Changes in brain activation in breast cancer patients depend on cognitive domain and treatment type.

BACKGROUND: Cognitive problems in breast cancer patients are common after systemic treatment, particularly chemotherapy. An increasing number of fMRI studies show altered brain activation in breast cancer patients after treatment, suggestive of neurotoxicity. Previous prospective fMRI studies administered a single cognitive task. The current study employed two task paradigms to evaluate whether treatment-induced changes depend on the probed cognitive domain. METHODS: Participants were breast cancer patients scheduled to receive systemic treatment (anthracycline-based chemotherapy +/- endocrine treatment, n = 28), or no systemic treatment (n = 24) and no-cancer controls (n = 31). Assessment took place before adjuvant treatment and six months after chemotherapy, or at similar intervals. Blood oxygen level dependent (BOLD) activation and performance were measured during an executive functioning task and an episodic memory task. Group-by-time interactions were analyzed using a flexible factorial design. RESULTS: Task performance did not differ between patient groups and did not change over time. Breast cancer patients who received systemic treatment, however, showed increased parietal activation compared to baseline with increasing executive functioning task load compared to breast cancer patients who did not receive systemic treatment. This hyperactivation was accompanied by worse physical functioning, higher levels of fatigue and more cognitive complaints. In contrast, in breast cancer patients who did not receive systemic treatment, parietal activation normalized over time compared to the other two groups. CONCLUSIONS: Parietal hyperactivation after systemic treatment in the context of stable levels of executive task performance is compatible with a compensatory processing account of hyperactivation or maintain adequate performance levels. This over-recruitment of brain regions depends on the probed cognitive domain and may represent a response to decreased neural integrity after systemic treatment. Overall these results suggest different neurobehavioral trajectories in breast cancer patients depending on treatment type.

Episodic memory function is affected by lifestyle factors: a 14-year follow-up study in an elderly population.

Understanding the relationship between memory function and lifestyle offers great opportunities for promoting beneficial lifestyle choices to foster healthy cognitive aging and for the development of intervention programs for older adults. We studied a cohort of older adults (age 65 and older) enrolled in the Longitudinal Aging Study Amsterdam, an ongoing prospective population-based research project. A total of 1,966 men and women participated in an episodic memory test every 3 years over a period of 14 years. Lifestyle habits were repeatedly assessed using self-report measures. Physical activity, light-to-moderate alcohol consumption, difficulties staying asleep, and social engagement were associated with better memory function over the course of 14 years. In contrast, smoking and long sleep duration were associated with worse memory function. These findings suggest that certain lifestyle factors can have long-term protective or harmful effects on memory function in aging individuals.

Immunometabolic dysregulation is associated with reduced cortical thickness of the anterior cingulate cortex.

BACKGROUND: Immunometabolic dysregulation (low-grade inflammation and metabolic dysregulation) has been associated with the onset and more severe course of multiple psychiatric disorders, partly due to neuroanatomical changes and impaired neuroplasticity. We examined the effect of multiple markers of immunometabolic dysregulation on hippocampal and amygdala volume and anterior cingulate cortex thickness in a large sample of patients with depression and/or anxiety and healthy subjects (N=283). METHODS: Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), c-reactive protein (CRP), triglyceride levels and HDL-cholesterol and genomic profile risk scores (GPRS) for immunometabolic dysregulation were determined in peripheral blood and T1 MRI scans were acquired at 3T. Regional brain volume and cortical thickness was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed to examine the relationship between immunometabolic dysregulation and brain volume/thickness across all subjects. RESULTS: Multiple immunometabolic dysregulation markers (i.e. triglyceride levels and inflammation) were associated with lower rostral ACC thickness across all subjects. IL-6 was inversely associated with hippocampal and amygdala volume in healthy subjects only. GPRS for immunometabolic dysregulation were not associated with brain volume or cortical thickness. CONCLUSIONS: Multiple serum, but not genetic immunometabolic dysregulation markers were found to relate to rostral ACC structure, suggesting that inflammation and metabolic dysregulation may impact the ACC through similar mechanisms.

Cognitive Impairment in a Subset of Breast Cancer Patients After Systemic Therapy-Results From a Longitudinal Study.

CONTEXT: Studies indicate adverse effects of breast cancer (BC) and cancer treatment on cognitive function. OBJECTIVES: To investigate the effects of systemic treatment on cognitive performance in BC patients. METHODS: Participants were BC patients scheduled to receive systemic treatment (BC + SYST; n = 31), or no systemic treatment (BC; n = 24) and no-cancer (NC) controls (n = 33). Neuropsychological examinations were used to study cognitive performance on 18 tests grouped into eight cognitive domains, before adjuvant treatment (T1) and six months after chemotherapy (T2), or at similar intervals. We also assessed health-related quality of life, anxiety and depression, mood, stress, and cognitive problems. Analysis of variance was used to assess group differences of cognitive performance and multivariate normative comparison to classify impairment, comparing scores of each participant against the distribution of the scores of NC controls. RESULTS: Of BC + SYST, 16% were cognitively impaired at T2, compared to 4% in BC and 6% in NC. Although not significant, we observed moderate effect sizes for worse performance in the BC + SYST group compared to NC (Flanker congruent [effect size {ES} = 0.44] and stimulus incongruent [ES = 0.44]) and compared to BC (Controlled Oral Word Association Test [ES = 0.47], digit span [ES = 0.41], and Hopkins Verbal Learning Test immediate [ES = 0.71] and delayed recall [ES = 0.65]). Cognitively impaired patients had a significantly lower estimated premorbid intelligence, worse physical and social functioning, and more distress at T2 compared to unimpaired patients. CONCLUSION: Our findings indicate that cognitive impairment after systemic treatment occurs in a subset of BC patients. The predictive value of demographic and psychosocial factors in cognitive impairment should be further investigated in a larger sample of impaired patients.

Does polycystic ovary syndrome affect cognition? A functional magnetic resonance imaging study exploring working memory.

OBJECTIVE: To study effects of overexposure to androgens and subsequent antiandrogenic treatment on brain activity during working memory processes in women with polycystic ovary syndrome (PCOS). DESIGN: In this longitudinal study, working memory function was evaluated with the use of functional magnetic resonance imaging (MRI) in women with PCOS before and after antiandrogenic treatment. SETTING: Department of reproductive medicine, university medical center. PATIENT(S): Fourteen women with PCOS and with hyperandrogenism and 20 healthy control women without any features of PCOS or other hormonal disorders. INTERVENTION(S): Antiandrogenic hormone treatment. MAIN OUTCOME MEASURE(S): Functional MRI response during a working memory task. RESULT(S): At baseline women with PCOS showed more activation than the control group within the right superior parietal lobe and the inferior parietal lobe during task (all memory conditions). Task performance (speed and accuracy) did not differ between the groups. After antiandrogenic treatment the difference in overall brain activity between the groups disappeared and accuracy in the high memory load condition of the working memory task increased in women with PCOS. CONCLUSION(S): Women with PCOS may need additional neural resources during a working memory task compared with women without PCOS, suggesting less efficient executive functioning. This inefficiency may have effects on daily life functioning of women with PCOS. Antiandrogenic treatment appears to have a beneficial effect on this area of cognitive functioning. CLINICAL TRIAL REGISTRATION NUMBER: NTR2493.

Puberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria.

Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since adolescence marks an important period for the development of executive functioning (EF), we determined whether the performance on the Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual differentiation of the brain, we determined whether untreated adolescents with GD showed sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n=8) with untreated MFs (n=10) or when comparing GnRHa treated female-to-males (suppressed FMs, n=12) with untreated FMs (n=10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in control boys (n=21) than control girls (n=24) during high task load ToL items in the bilateral precuneus and a trend (p<0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD.

Multimodal MRI and cognitive function in patients with breast cancer prior to adjuvant treatment--the role of fatigue.

An increasing body of literature indicates that chemotherapy (ChT) for breast cancer (BC) is associated with adverse effects on the brain. Recent research suggests that cognitive and brain function in patients with BC may already be compromised before the start of chemotherapy. This is the first study combining neuropsychological testing, patient-reported outcomes, and multimodal magnetic resonance imaging (MRI) to examine pretreatment cognition and various aspects of brain function and structure in a large sample. Thirty-two patients with BC scheduled to receive ChT (pre-ChT+), 33 patients with BC not indicated to undergo ChT (pre-ChT-), and 38 no-cancer controls (NCs) were included. The examination consisted of a neuropsychological test battery, self-reported aspects of psychosocial functioning, and multimodal MRI. Patients with BC reported worse scores on several aspects of quality of life, such as higher levels of fatigue and stress. However, cortisol levels were not elevated in the patient groups compared to the control group. Overall cognitive performance was lower in the pre-ChT+ and the pre-ChT- groups compared to NC. Further, patients demonstrated prefrontal hyperactivation with increasing task difficulty on a planning task compared to NC, but not during a memory task. White matter integrity was lower in both patient groups. No differences in regional brain volume and brain metabolites were found. The cognitive and imaging data converged to show that symptoms of fatigue were associated with the observed abnormalities; the observed differences were no longer significant when fatigue was accounted for. This study suggests that cancer-related psychological or biological processes may adversely impact cognitive functioning and associated aspects of brain structure and function before the start of adjuvant treatment. Our findings stress the importance to further explore the processes underlying the expression of fatigue and to study whether it has a contributory role in subsequent treatment-related cognitive decline.

Very Late Treatment-Related Alterations in Brain Function of Breast Cancer Survivors.

Although adjuvant chemotherapy (CT) for breast cancer (BC) is associated with very late side-effects on cognition and brain function, studies on adverse effects of specific treatment regimens are scarce. Here, neurotoxicity profiles after different treatment strategies were compared in BC survivors randomized to high-dose (HI) or conventional-dose (CON-) CT, in women treated with radiotherapy (RT) -only and a healthy control (HC) group. We administered a neurocognitive test battery, a planning fMRI task (Tower of London) and episodic memory fMRI task (Paired Associates paradigm) in BC survivors who received CON-CT (n=24) and HC (n=27). Data were compared to BC survivors who received HI-CT (n=17) and RT-only (n=15) and who were previously assessed. Testing took place ±11.5 years post-CT. Furthermore, neurocognitive data were compared to neurocognitive data acquired ≤2 years post-treatment. Cognitive assessment revealed sustained cognitive decline in 10.5% of HI-CT, 8.3% of CON-CT, 6.7% of RT-only patients and 0% in the HC. Hypoactivation was found in task-related prefrontal and parietal areas for both CT-groups versus RT-only, with HI-CT showing more pronounced hypoactivation than CON-CT, combined with worse task performance. RT-only survivors performed at a similar level to HC while showing hyperactivation in task-related brain areas. Long after treatment, CT is associated with cognitive problems and task-related hypoactivation that depend on the specific cytotoxic regimen. This worse performance in patients who received CT could be explained by impaired brain functioning that is more severe with more intense CT.

Brain volume in male patients with recent onset schizophrenia with and without cannabis use disorders.

BACKGROUND: Schizophrenia is highly comorbid with cannabis use disorders (CUDs), and this comorbidity is associated with an unfavourable course. Early onset or frequent cannabis use may influence brain structure. A key question is whether comorbid CUDs modulate brain morphology alterations associated with schizophrenia. METHODS: We used surface-based analysis to measure the brain volume, cortical thickness and cortical surface area of a priori-defined brain regions (hippocampus, amygdala, thalamus, caudate, putamen, orbitofrontal cortex, anterior cingulate cortex, insula, parahippocampus and fusiform gyrus) in male patients with schizophrenia or related disorders with and without comorbid CUDs and matched healthy controls. Associations between age at onset and frequency of cannabis use with regional grey matter volume were explored. RESULTS: We included 113 patients with (CUD, n = 80) and without (NCUD, n = 33) CUDs and 84 controls in our study. As expected, patients with schizophrenia (with or without a CUD) had smaller volumes of most brain regions (amygdala, putamen, insula, parahippocampus and fusiform gyrus) than healthy controls, and differences in cortical volume were mainly driven by cortical thinning. Compared with the NCUD group, the CUD group had a larger volume of the putamen, possibly driven by polysubstance use. No associations between age at onset and frequency of use with regional grey matter volumes were found. LIMITATIONS: We were unable to correct for possible confounding effects of smoking or antipsychotic medication. CONCLUSION: Patients with psychotic disorders and comorbid CUDs have larger putamen volumes than those without CUDs. Future studies should elaborate whether a large putamen represents a risk factor for the development of CUDs or whether (poly)substance use causes changes in putamen volume.

GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans.

Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We hypothesized that food intake reduction after GLP-1 receptor activation is mediated through appetite- and reward-related brain areas. Obese T2DM patients and normoglycemic obese and lean individuals (n = 48) were studied in a randomized, crossover, placebo-controlled trial. Using functional MRI, we determined the acute effects of intravenous administration of the GLP-1 receptor agonist exenatide, with or without prior GLP-1 receptor blockade using exendin 9-39, on brain responses to food pictures during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese versus lean subjects showed increased brain responses to food pictures in appetite- and reward-related brain regions (insula and amygdala). Exenatide versus placebo decreased food intake and food-related brain responses in T2DM patients and obese subjects (in insula, amygdala, putamen, and orbitofrontal cortex). These effects were largely blocked by prior GLP-1 receptor blockade using exendin 9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss.

Physiological and endocrine reactions to psychosocial stress in alcohol use disorders: duration of abstinence matters.

BACKGROUND: Recent research findings suggest that heavy alcohol use is associated with alterations of the hypothalamic-pituitary-adrenal axis and autonomic nervous system function and that early abstinence is associated with blunted stress responsiveness. METHODS: This study investigated abstinent alcohol-dependent participants (AADs; n = 31), who had a drinking history of levels about 97 drinks per week (abstinence range: 2 weeks to 24 months), actively drinking problem drinkers (PRDs; n = 23), who reported drinking levels about 47 drinks per week and who were abstinent for at least 24 hours, and healthy control (HC) participants (n = 20). It was investigated how participants responded to a psychosocial stress task. All of them were exposed to a modified Trier Social Stress Test. Salivary cortisol, heart rate, skin conductance levels, and negative affect were assessed as stress indicators. RESULTS: AADs showed stress reactions comparable to HC participants, whereas active PRDs showed increased heart rate and cortisol stress responses. In the AAD group, duration of abstinence was positively related to cortisol stress responses. CONCLUSIONS: Active PRDs showed increased responses to psychosocial stress. Results indicate that duration of abstinence is a key factor when analyzing and interpreting stress responses in alcohol abuse and dependence.

Individual differences in decision making and reward processing predict changes in cannabis use: a prospective functional magnetic resonance imaging study.

Decision-making deficits are thought to play an important role in the development and persistence of substance use disorders. Individual differences in decision-making abilities and their underlying neurocircuitry may, therefore, constitute an important predictor for the course of substance use and the development of substance use disorders. Here, we investigate the predictive value of decision making and neural mechanisms underlying decision making for future cannabis use and problem severity in a sample of heavy cannabis users. Brain activity during a monetary decision-making task (Iowa gambling task) was compared between 32 heavy cannabis users and 41 matched non-using controls using functional magnetic resonance imaging. In addition, within the group of heavy cannabis users, associations were examined between task-related brain activations, cannabis use and cannabis use-related problems at baseline, and change in cannabis use and problem severity after a 6-month follow-up. Despite normal task performance, heavy cannabis users compared with controls showed higher activation during wins in core areas associated with decision making. Moreover, within the group of heavy cannabis users, win-related activity and activity anticipating loss outcomes in areas generally involved in executive functions predicted change in cannabis use after 6 months. These findings are consistent with previous studies and point to abnormal processing of motivational information in heavy cannabis users. A new finding is that individuals who are biased toward immediate rewards have a higher probability of increasing drug use, highlighting the importance of the relative balance between motivational processes and regulatory executive processes in the development of substance use disorders.

The role of dopamine in inhibitory control in smokers and non-smokers: a pharmacological fMRI study.

Contemporary theoretical models of substance dependence posit that deficits in inhibitory control play an important role in substance dependence. The neural network underlying inhibitory control and its association with substance dependence have been widely investigated. However, the pharmacology of inhibitory control is still insufficiently clear. The aims of the current study were twofold. First, we investigated the role of dopamine in inhibitory control and associated brain activation. Second, the proposed link between dopamine and impaired inhibitory control in nicotine dependence was investigated by comparing smokers and non-smoking controls. Haloperidol (2 mg), a dopamine D2/D3 receptor antagonist, and placebo were administered to 25 smokers and 25 non-smoking controls in a double-blind randomized cross-over design while performing a Go/NoGo task during fMRI scanning. Haloperidol reduced NoGo accuracy and associated brain activation in the ACC, right SFG and left IFG, showing that optimal dopamine levels are crucial to effectively implement inhibitory control. In addition, smokers showed behavioral deficits on the Go/NoGo task as well as hypoactivity in the left IFG, right MFG and ACC after placebo, supporting the hypothesis of a hypoactive prefrontal system in smokers. Haloperidol had a stronger impact on prefrontal brain activation in non-smoking controls compared to smokers, which is in line with the inverted 'U' curve theory of dopamine and cognitive control. The current findings suggest that altered baseline dopamine levels in addicted individuals may contribute to the often observed reduction in inhibitory control in these populations.

Brain activation associated with attentional bias in smokers is modulated by a dopamine antagonist.

Attentional bias in substance-dependent individuals is the tendency to automatically direct the attention to substance-related cues in the environment. Attentional bias is known to be associated with clinical measures such as relapse or successful quitting in smokers. It has been suggested that attentional bias emerges as a consequence of dopaminergic activity evoked by substance-related cues. The current functional magnetic resonance imaging study employed a dopaminergic challenge in order to test whether brain activation associated with attentional bias in smokers could be modulated by a dopamine antagonist. A total of 25 smokers were compared with 24 controls. Participants were scanned twice while performing a pictorial attentional bias task. Haloperidol (2 mg), a selective D2/D3 dopamine antagonist, or placebo was orally administered 4 h before each scanning session in a double-blind randomized cross-over design. Imaging analyses were performed in a priori selected regions of interest. Results showed that smokers had enhanced brain activation compared with controls in the dorsal anterior cingulate cortex (dACC), right dorsolateral prefrontal cortex (r-DLPFC), and left superior parietal lobe (I-SPL) after placebo. Group × medication interactions were found in the dACC and r-DLPFC, with no differences between groups in these regions after haloperidol. The current findings suggest that a pharmacologically induced reduction in dopamine normalizes brain activation associated with attentional bias in the dACC and DLPFC in smokers, probably because salience of these cues is no longer detected when dopamine activity is reduced.