Corinde E. Wiers

Effects of cognitive bias modification training on neural alcohol cue reactivity in alcohol dependence

OBJECTIVE In alcohol-dependent patients, alcohol cues evoke increased activation in mesolimbic brain areas, such as the nucleus accumbens and the amygdala. Moreover, patients show an alcohol approach bias, a tendency to more quickly approach than avoid alcohol cues. Cognitive bias modification training, which aims to retrain approach biases, has been shown to reduce alcohol craving and relapse rates. The authors investigated effects of this training on cue reactivity in alcohol-dependent patients. METHOD In a double-blind randomized design, 32 abstinent alcohol-dependent patients received either bias modification training or sham training. Both trainings consisted of six sessions of the joystick approach-avoidance task; the bias modification training entailed pushing away 90% of alcohol cues and 10% of soft drink cues, whereas this ratio was 50/50 in the sham training. Alcohol cue reactivity was measured with functional MRI before and after training. RESULTS Before training, alcohol cue-evoked activation was observed in the amygdala bilaterally, as well as in the right nucleus accumbens, although here it fell short of significance. Activation in the amygdala correlated with craving and arousal ratings of alcohol stimuli; correlations in the nucleus accumbens again fell short of significance. After training, the bias modification group showed greater reductions in cue-evoked activation in the amygdala bilaterally and in behavioral arousal ratings of alcohol pictures, compared with the sham training group. Decreases in right amygdala activity correlated with decreases in craving in the bias modification but not the sham training group. CONCLUSIONS These findings provide evidence that cognitive bias modification affects alcohol cue-induced mesolimbic brain activity. Reductions in neural reactivity may be a key underlying mechanism of the therapeutic effectiveness of this training.

Neural Correlates of Alcohol-Approach Bias in Alcohol Addiction: the Spirit is Willing but the Flesh is Weak for Spirits

Behavioral studies have shown an alcohol-approach bias in alcohol-dependent patients: the automatic tendency to faster approach than avoid alcohol compared with neutral cues, which has been associated with craving and relapse. Although this is a well-studied psychological phenomenon, little is known about the brain processes underlying automatic action tendencies in addiction. We examined 20 alcohol-dependent patients and 17 healthy controls with functional magnetic resonance imaging (fMRI), while performing an implicit approach-avoidance task. Participants pushed and pulled pictorial cues of alcohol and soft-drink beverages, according to a content-irrelevant feature of the cue (landscape/portrait). The critical fMRI contrast regarding the alcohol-approach bias was defined as (approach alcohol>avoid alcohol)>(approach soft drink>avoid soft drink). This was reversed for the avoid-alcohol contrast: (avoid alcohol>approach alcohol)>(avoid soft drink>approach soft drink). In comparison with healthy controls, alcohol-dependent patients had stronger behavioral approach tendencies for alcohol cues than for soft-drink cues. In the approach, alcohol fMRI contrast patients showed larger blood-oxygen-level-dependent responses in the nucleus accumbens and medial prefrontal cortex, regions involved in reward and motivational processing. In alcohol-dependent patients, alcohol-craving scores were positively correlated with activity in the amygdala for the approach-alcohol contrast. The dorsolateral prefrontal cortex was not activated in the avoid-alcohol contrast in patients vs controls. Our data suggest that brain regions that have a key role in reward and motivation are associated with the automatic alcohol-approach bias in alcohol-dependent patients.

Effects of cognitive bias modification training on neural signatures of alcohol approach tendencies in male alcohol-dependent patients

Alcohol‐dependent patients have been shown to faster approach than avoid alcohol stimuli on the Approach Avoidance Task (AAT). This so‐called alcohol approach bias has been associated with increased brain activation in the medial prefrontal cortex and nucleus accumbens. Cognitive bias modification (CBM) has been used to retrain the approach bias with the clinically relevant effect of decreasing relapse rates one year later. The effects of CBM on neural signatures of approach/avoidance tendencies remain hitherto unknown. In a double‐blind placebo‐controlled design, 26 alcohol‐dependent in‐patients were assigned to a CBM or a placebo training group. Both groups performed the AAT for three weeks: in CBM training, patients pushed away 90 percent of alcohol cues; this rate was 50 percent in placebo training. Before and after training, patients performed the AAT offline, and in a 3 T magnetic resonance imaging scanner. The relevant neuroimaging contrast for the alcohol approach bias was the difference between approaching versus avoiding alcohol cues relative to soft drink cues: [(alcohol pull > alcohol push)  > (soft drink pull > soft drink push)]. Before training, both groups showed significant alcohol approach bias‐related activation in the medial prefrontal cortex. After training, patients in the CBM group showed stronger reductions in medial prefrontal cortex activation compared with the placebo group. Moreover, these reductions correlated with reductions in approach bias scores in the CBM group only. This suggests that CBM affects neural mechanisms involved in the automatic alcohol approach bias, which may be important for the clinical effectiveness of CBM.

Cognitive neuroscience of cognitive retraining for addiction medicine: From mediating mechanisms to questions of efficacy.

Cognitive retraining or cognitive bias modification (CBM) involves having subjects repeatedly perform a computerized task designed to reduce the impact of automatic processes that lead to harmful behavior. We first discuss the theory underlying CBM and provide a brief overview of important research progress in its application to addiction. We then focus on cognitive- and neural-mediating mechanisms. We consider recent criticism of both CBM and its theoretical foundations. Evaluations of CBM could benefit from considering theory-driven factors that may determine variations in efficacy, such as motivation. Concerning theory, while there is certainly room for fundamental advances in current models, we argue that the basic view of impulsive behavior and its control remains a useful and productive heuristic. Finally, we briefly discuss some interesting new directions for CBM research: enhancement of training via transcranial direct current stimulation, online training, and gamification, i.e., the use of gameplay elements to increase motivation.

Cannabis Abusers Show Hypofrontality and Blunted Brain Responses to a Stimulant Challenge in Females but not in Males

The extent to which cannabis is deleterious to the human brain is not well understood. Here, we test whether cannabis abusers (CA) have impaired frontal function and reactivity to dopaminergic signaling, which are fundamental to relapse in addiction. We measured brain glucose metabolism using PET and [18F]FDG both at baseline (placebo) and after challenge with methylphenidate (MP), a dopamine-enhancing drug, in 24 active CA (50% female) and 24 controls (HC; 50% female). Results show that (i) CA had lower baseline glucose metabolism than HC in frontal cortex including anterior cingulate, which was associated with negative emotionality. (ii) MP increased whole-brain glucose metabolism in HC but not in CA; and group by challenge effects were most profound in putamen, caudate, midbrain, thalamus, and cerebellum. In CA, MP-induced metabolic increases in putamen correlated negatively with addiction severity. (iii) There were significant gender effects, such that both the group differences at baseline in frontal metabolism and the attenuated regional brain metabolic responses to MP were observed in female CA but not in male CA. As for other drug addictions, reduced baseline frontal metabolism is likely to contribute to relapse in CA. The attenuated responses to MP in midbrain and striatum are consistent with decreased brain reactivity to dopamine stimulation and might contribute to addictive behaviors in CA. The gender differences suggest that females are more sensitive than males to the adverse effects of cannabis in brain.

Neuroimaging the Effectiveness of Substance Use Disorder Treatments.

Neuroimaging techniques to measure the function and biochemistry of the human brain such as positron emission tomography (PET), proton magnetic resonance spectroscopy (1H MRS), and functional magnetic resonance imaging (fMRI), are powerful tools for assessing neurobiological mechanisms underlying the response to treatments in substance use disorders. Here, we review the neuroimaging literature on pharmacological and behavioral treatment in substance use disorder. We focus on neural effects of medications that reduce craving (e.g., naltrexone, bupropion hydrochloride, baclofen, methadone, varenicline) and that improve cognitive control (e.g., modafinil, N-acetylcysteine), of behavioral treatments for substance use disorders (e.g., cognitive bias modification training, virtual reality, motivational interventions) and neuromodulatory interventions such as neurofeedback and transcranial magnetic stimulation. A consistent finding for the effectiveness of therapeutic interventions identifies the improvement of executive control networks and the dampening of limbic activation, highlighting their values as targets for therapeutic interventions in substance use disorders.

Methylation and the human brain: towards a new discipline of imaging epigenetics

The field of imaging genetics traditionally studies unidirectional associations between genes, brain functioning, and behavior. In a recent study by Ursini et al. (J Neurosci 31:6692–6698, 2011), imaging genetics methods are combined with epigenetic marks in living human beings. This approach may lead to a new field of imaging epigenetics, providing more mechanistic insight into causal pathways of how gene and environment interact and affect brain development.

Effects of depressive symptoms and peripheral DAT methylation on neural reactivity to alcohol cues in alcoholism

In alcohol-dependent (AD) patients, alcohol cues induce strong activations in brain areas associated with alcohol craving and relapse, such as the nucleus accumbens (NAc) and amygdala. However, little is known about the influence of depressive symptoms, which are common in AD patients, on the brain’s reactivity to alcohol cues. The methylation state of the dopamine transporter gene (DAT) has been associated with alcohol dependence, craving and depression, but its influence on neural alcohol cue reactivity has not been tested. Here, we compared brain reactivity to alcohol cues in 38 AD patients and 17 healthy controls (HCs) using functional magnetic resonance imaging and assessed the influence of depressive symptoms and peripheral DAT methylation in these responses. We show that alcoholics with low Beck’s Depression Inventory scores (n=29) had higher cue-induced reactivity in NAc and amygdala than those with mild/moderate depression scores (n=9), though subjective perception of craving was higher in those with mild/moderate depression scores. We corroborated a higher DAT methylation in AD patients than HCs, and showed higher DAT methylation in AD patients with mild/moderate than low depression scores. Within the AD cohort, higher methylation predicted craving and, at trend level (P=0.095), relapse 1 year after abstinence. Finally, we show that amygdala cue reactivity correlated with craving and DAT methylation only in AD patients with low depression scores. These findings suggest that depressive symptoms and DAT methylation are associated with alcohol craving and associated brain processes in alcohol dependence, which may have important consequences for treatment. Moreover, peripheral DAT methylation may be a clinically relevant biomarker in AD patients.

Reduced sleep duration mediates decreases in striatal D2/D3 receptor availability in cocaine abusers.

Neuroimaging studies have documented reduced striatal dopamine D2/D3 receptor (D2/D3R) availability in cocaine abusers, which has been associated with impaired prefrontal activity and vulnerability for relapse. However, the mechanism(s) underlying the decreases in D2/D3R remain poorly understood. Recent studies have shown that sleep deprivation is associated with a downregulation of striatal D2/D3R in healthy volunteers. As cocaine abusers have disrupted sleep patterns, here we investigated whether reduced sleep duration mediates the relationship between cocaine abuse and low striatal D2/D3R availability. We used positron emission tomography with [11C]raclopride to measure striatal D2/D3R availability in 24 active cocaine abusers and 21 matched healthy controls, and interviewed them about their daily sleep patterns. Compared with controls, cocaine abusers had shorter sleep duration, went to bed later and reported longer periods of sleep disturbances. In addition, cocaine abusers had reduced striatal D2/D3R availability. Sleep duration predicted striatal D2/D3R availability and statistically mediated the relationship between cocaine abuse and striatal D2/D3R availability. These findings suggest that impaired sleep patterns contribute to the low striatal D2/D3R availability in cocaine abusers. As sleep impairments are similarly observed in other types of substance abusers (for example, alcohol and methamphetamine), this mechanism may also underlie reductions in D2/D3R availability in these groups. The current findings have clinical implications suggesting that interventions to improve sleep patterns in cocaine abusers undergoing detoxification might be beneficial in improving their clinical outcomes.

PET imaging for addiction medicine: From neural mechanisms to clinical considerations

Positron emission tomography (PET) has been shown to be an effective imaging technique to study neurometabolic and neurochemical processes involved in addiction. That is, PET has been used to research neurobiological differences in substance abusers versus healthy controls and the pharmacokinetics and pharmacodynamics of abused drugs. Over the past years, the research scope has shifted to investigating neurobiological effects of abstinence and treatment, and their predictive power for relapse and other clinical outcomes. This chapter provides an overview of PET methodology, recent human PET studies on drug addiction and their implications for clinical treatment.