Mira Bühler

Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery

RationaleIn nicotine-dependent subjects, cues related to smoking elicit activity in brain regions linked to attention, memory, emotion and motivation. Cue-induced brain activation is associated with self-reported craving but further correlates are widely unknown.ObjectivesThis study was conducted to investigate whether brain activity elicited by smoking cues increases with severity of nicotine dependence and intensity of cue-elicited craving.MethodsTen healthy male smokers whose degree of nicotine dependence ranged from absent to severe were investigated. Visual smoking cues and neutral stimuli were presented in a block design during functional magnetic resonance imaging (fMRI). Using multiple linear regression analysis, the blood oxygen level dependent (BOLD) response to smoking cues was correlated with severity of nicotine dependence assessed with the Fagerström Test of Nicotine Dependence (FTND) and with cue-induced craving.ResultsSignificant positive correlations between the BOLD activity and FTND scores were found in brain areas related to visuospatial attention (anterior cingulate cortex, parietal cortex, parahippocampal gyrus and cuneus) and in regions involved in motor preparation and imagery (primary and premotor cortex, supplementary motor area). Intensity of cue-induced craving was significantly associated with greater BOLD activation in mesocorticolimbic areas engaged in incentive motivation and in brain regions related to episodic memory.ConclusionsOur study suggests that severity of nicotine dependence and intensity of craving are independently associated with cue-induced brain activation in separate neuronal networks. The observed association between severity of dependence and brain activity in regions involved in allocation of attention, motor preparation and imagery might reflect preparation of automated drug taking behavior thereby facilitating cue-induced relapse.

Initial, habitual and compulsive alcohol use is characterized by a shift of cue processing from ventral to dorsal striatum

AIMS During the development of drug addiction, initial hedonic effects decrease when substance use becomes habitual and ultimately compulsive. Animal research suggests that these changes are represented by a transition from prefrontal cortical control to subcortical striatal control and within the striatum from ventral to dorsal domains of the striatum, but only limited evidence exists in humans. In this study we address this hypothesis in the context of alcohol dependence. DESIGN, SETTING AND PARTICIPANTS Non-abstinent heavy social drinkers (n = 21, 5.0 ± 1.5 drinks/day, 13 of them were alcohol-dependent according to DSM-IV) and light social drinkers (n = 10, 0.4 ± 0.4 drinks/day) were examined. MEASUREMENTS We used a cue-reactivity functional magnetic resonance imaging (fMRI) design during which pictures of alcoholic beverages and neutral control stimuli were presented. FINDINGS In the dorsal striatum heavy drinkers showed significant higher activations compared to light drinkers, whereas light social drinkers showed higher cue-induced fMRI activations in the ventral striatum and in prefrontal areas compared to heavy social drinkers [region of interest analyses, P < 0.05 false discovery rate (FDR)-corrected]. Correspondingly, ventral striatal activation in heavy drinkers correlated negatively with obsessive-compulsive craving, and furthermore we found a positive association between cue-induced activation in the dorsal striatum and obsessive-compulsive craving in all participants. CONCLUSIONS In line with our hypothesis we found higher cue-induced activation of the ventral striatum in social compared to heavy drinkers, and higher dorsal striatal activation in heavy drinkers. Increased prefrontal activation may indicate that social drinkers activate cortical control when viewing alcohol cues, which may prevent the development of heavy drinking or alcohol dependence. Our results suggest differentiating treatment research depending on whether alcohol use is hedonic or compulsive.

Alcohol and the Human Brain: A Systematic Review of Different Neuroimaging Methods

BACKGROUND Imaging techniques have been in widespread use in the scientific community for more than 3 decades. They facilitate noninvasive, in vivo studies of the human brain in both healthy and diseased persons. These brain-imaging techniques have contributed significantly to our understanding of the effects of alcohol abuse and dependence on structural and functional changes in the human brain. A systematic review summarizing these contributions has not previously been conducted, and this is the goal of the current paper. METHODS The databases PubMed, PsycINFO, and PSYNDEX were searched using central key words. Fulfilling the inclusion criteria were 140 functional and structural imaging studies, together comprising data from more than 7,000 patients and controls. The structural imaging techniques we considered were cranial computerized tomography and various magnetic resonance imaging-based techniques, including voxel-based morphometry, deformation-based morphometry, diffusion tensor magnetic resonance imaging, and diffusion-weighted magnetic resonance imaging. The functional methods considered were magnetic resonance spectroscopy, positron emission tomography, single photon emission computed tomography, and functional magnetic resonance imaging. RESULTS Results from studies using structural imaging techniques have revealed that chronic alcohol use is accompanied by volume reductions of gray and white matter, as well as microstructural disruption of various white matter tracts. These changes are partially reversible following abstinence. Results from functional imaging methods have revealed metabolic changes in the brain, lower glucose metabolism, and disruptions of the balance of neurotransmitter systems. Additionally, functional imaging methods have revealed increased brain activity in the mesocorticolimbic system in response to alcohol-themed pictures relative to nondrug-associated stimuli, which might be of predictive value with regard to relapse. CONCLUSIONS There has been tremendous progress in the development of imaging technologies. Use of these technologies has clearly demonstrated the structural and functional brain abnormalities that can occur with chronic alcohol use. The study of the alcoholic brain provides an heuristic model which furthers our understanding of neurodegenerative changes in general, as well as their partial reversibility with sustained abstinence. Additionally, functional imaging is poised to become an important tool for generating predictions about individual brain functioning, which can then be used as a basis for personalized medicine.

Gene–gene effects on central processing of aversive stimuli

Emotional reactivity and regulation are fundamental to human behavior. As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene–gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli. These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene. Recently, it has been proposed that 5-HTT expression is not only affected by the common S/L variant of 5-HTTLPR but also by an A to G substitution. Using functional magnetic resonance imaging, we assessed the effects of COMT Val158Met and both 5-HTT genotypes on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 48 healthy subjects. Based on previous studies, the analysis of genotype effects was restricted to limbic brain areas. To determine allele-dose effects, the number of COMT Met158 alleles (i.e., lower activity of COMT) and the number of 5-HTT low expressing alleles (S and G) was correlated with the blood oxygen level-dependent (BOLD) response to pleasant or unpleasant stimuli compared to neutral stimuli. We observed an additive effect of COMT and both 5-HTT polymorphisms, accounting for 40% of the inter-individual variance in the averaged BOLD response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli. Effects of 5-HTT and COMT genotypes did not affect brain processing of pleasant stimuli. These data indicate that functional brain imaging may be used to assess the interaction of multiple genes on the function of neuronal networks.

Nicotine Dependence Is Characterized by Disordered Reward Processing in a Network Driving Motivation

BACKGROUND Drug addiction is characterized by an unhealthy priority for drug consumption with a compulsive, uncontrolled drug-intake pattern due to a disordered motivational system. However, only some individuals become addicted, whereas others maintain regular but controlled drug use. Whether the transition occurs might depend on how individuals process drug relative to nondrug reward. METHODS We applied functional magnetic resonance imaging to measure mesocorticolimbic activity to stimuli predicting monetary or cigarette reward, together with behavioral assessment of subsequent motivation to obtain the respective reward on a trial-by-trial basis, in 21 nicotine-dependent and 21 nondependent, occasional smokers. RESULTS Occasional smokers showed increased reactivity of the mesocorticolimbic system to stimuli predicting monetary reward relative to cigarette reward and subsequently spent more effort to obtain money. In the group of dependent smokers, we found equivalent anticipatory activity and subsequent instrumental response rates for both reward types. Additionally, anticipatory mesocorticolimbic activation predicted subsequent motivation to obtain reward. CONCLUSIONS This imbalance in the incentive salience of drug relative to nondrug reward-predicting cues, in a network that drives motivation to obtain reward, could represent a central mechanism of drug addiction.

Effects of Cue-Exposure Treatment on Neural Cue Reactivity in Alcohol Dependence: A Randomized Trial

BACKGROUND In alcohol-dependent patients, alcohol-associated cues elicit brain activation in mesocorticolimbic networks involved in relapse mechanisms. Cue-exposure based extinction training (CET) has been shown to be efficacious in the treatment of alcoholism; however, it has remained unexplored whether CET mediates its therapeutic effects via changes of activity in mesolimbic networks in response to alcohol cues. In this study, we assessed CET treatment effects on cue-induced responses using functional magnetic resonance imaging (fMRI). METHODS In a randomized controlled trial, abstinent alcohol-dependent patients were randomly assigned to a CET group (n = 15) or a control group (n = 15). All patients underwent an extended detoxification treatment comprising medically supervised detoxification, health education, and supportive therapy. The CET patients additionally received nine CET sessions over 3 weeks, exposing the patient to his/her preferred alcoholic beverage. Cue-induced fMRI activation to alcohol cues was measured at pretreatment and posttreatment. RESULTS Compared with pretreatment, fMRI cue-reactivity reduction was greater in the CET relative to the control group, especially in the anterior cingulate gyrus and the insula, as well as limbic and frontal regions. Before treatment, increased cue-induced fMRI activation was found in limbic and reward-related brain regions and in visual areas. After treatment, the CET group showed less activation than the control group in the left ventral striatum. CONCLUSIONS The study provides first evidence that an exposure-based psychotherapeutic intervention in the treatment of alcoholism impacts on brain areas relevant for addiction memory and attentional focus to alcohol-associated cues and affects mesocorticolimbic reward pathways suggested to be pathophysiologically involved in addiction.

Association of Leptin With Food Cue–Induced Activation in Human Reward Pathways

CONTEXT Overlapping neurobiological pathways between obesity and addiction disorders are currently in discussion. Whereas the hypothalamic regulation of energy homeostasis by endocrine feedback signals has been widely investigated, its interplay with mesolimbic reward-associated pathways represents a rich field of future research. OBJECTIVE To assess changes in regional brain activation in response to food-related cues in association with body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and the plasma concentration of the appetite-regulating peptide leptin. DESIGN Case-control study. SETTING Academic addiction and brain imaging center, Central Institute of Mental Health, Mannheim, Germany. PARTICIPANTS Twenty-one obese subjects (BMI >30) and 23 age- and sex-matched nonobese control subjects (BMI 18.5-24.0) recruited by advertisements. MAIN OUTCOME MEASURES Regional brain activation (blood oxygen level-dependent response) in response to visual cue presentation and association of the brain activation with BMI and plasma leptin concentration. RESULTS Significant positive relationships were observed for food cue-induced brain activations in the ventral striatum in association with the plasma concentration of leptin (r = 0.27; P = .04) and with BMI (r = 0.47; P = .001). CONCLUSIONS Data suggest a physiological role of satiety factors in modulating the responsivity of mesolimbic circuits to food cues. Moreover, an altered homeostatic feedback regulation of reward pathways might explain addictionlike behavior and the inability of obese patients to adapt food intake to physiological needs.

Does erotic stimulus presentation design affect brain activation patterns? Event-related vs. blocked fMRI designs

BackgroundExisting brain imaging studies, investigating sexual arousal via the presentation of erotic pictures or film excerpts, have mainly used blocked designs with long stimulus presentation times.MethodsTo clarify how experimental functional magnetic resonance imaging (fMRI) design affects stimulus-induced brain activity, we compared brief event-related presentation of erotic vs. neutral stimuli with blocked presentation in 10 male volunteers.ResultsBrain activation differed depending on design type in only 10% of the voxels showing task related brain activity. Differences between blocked and event-related stimulus presentation were found in occipitotemporal and temporal regions (Brodmann Area (BA) 19, 37, 48), parietal areas (BA 7, 40) and areas in the frontal lobe (BA 6, 44).ConclusionOur results suggest that event-related designs might be a potential alternative when the core interest is the detection of networks associated with immediate processing of erotic stimuli.Additionally, blocked, compared to event-related, stimulus presentation allows the emergence and detection of non-specific secondary processes, such as sustained attention, motor imagery and inhibition of sexual arousal.

Auditory working memory load impairs visual ventral stream processing: Toward a unified model of attentional load

Attentional interference between tasks performed in parallel is known to have strong and often undesired effects. As yet, however, the mechanisms by which interference operates remain elusive. A better knowledge of these processes may facilitate our understanding of the effects of attention on human performance and the debilitating consequences that disruptions to attention can have. According to the load theory of cognitive control, processing of task-irrelevant stimuli is increased by attending in parallel to a relevant task with high cognitive demands. This is due to the relevant task engaging cognitive control resources that are, hence, unavailable to inhibit the processing of task-irrelevant stimuli. However, it has also been demonstrated that a variety of types of load (perceptual and emotional) can result in a reduction of the processing of task-irrelevant stimuli, suggesting a uniform effect of increased load irrespective of the type of load. In the present study, we concurrently presented a relevant auditory matching task [n-back working memory (WM)] of low or high cognitive load (1-back or 2-back WM) and task-irrelevant images at one of three object visibility levels (0%, 50%, or 100%). fMRI activation during the processing of the task-irrelevant visual stimuli was measured in the lateral occipital cortex and found to be reduced under high, compared to low, WM load. In combination with previous findings, this result is suggestive of a more generalized load theory, whereby cognitive load, as well as other types of load (e.g., perceptual), can result in a reduction of the processing of task-irrelevant stimuli, in line with a uniform effect of increased load irrespective of the type of load.

Nicotine increases neural response to unpleasant stimuli and anxiety in non-smokers.

Studies in smokers suggest that nicotine might exert anxiolytic, stress‐dampening and mood‐enhancing effects and beneficially influences neural processing of affective information. Regarding non‐smokers, results are inconsistent, and no data exist on the effect of nicotine on neural emotion processing. We applied functional magnetic resonance imaging (fMRI) to assess the influence of nicotine on brain activation during processing of emotional stimuli in 31 non‐smokers with a maximum lifetime cigarette consumption of 20 cigarettes. Participants were subjected to two fMRI scans with event‐related presentations of images taken from the International Affective Picture System, receiving nicotine (2 mg) and placebo gums in a double‐blinded, randomized cross‐over design. Furthermore, subjective affect was assessed. Nicotine increased brain activity in response to unpleasant stimuli in the amygdala, anterior cingulate cortex (ACC) and basal ganglia, whereas processing of pleasant stimuli was not altered. Psychophysiological interaction (PPI) analyses revealed that nicotine increased connectivity between the amygdala and the perigenual ACC (pACC) during processing of unpleasant stimuli and decreased connectivity between those structures during processing of pleasant stimuli. Participants reported higher state anxiety under nicotine than placebo. A single dose of nicotine acted as a stressor in non‐smokers, leading to increased anxiety and neural activation elicited by unpleasant stimuli as well as altered connectivity within the amygdala–pACC circuit. Besides the possibility that reactions to nicotine may differ between non‐smokers and smokers due to tolerance and neuroadaptive processes that occur during prolonged nicotine use, a priori differences in smokers and non‐smokers might potentially explain diverse effects of nicotine on affect and emotional reactivity.