For a minority of alcohol users, the initial sip of alcohol marks the start of a life-threatening process. This thesis studies cognitive mechanisms pertinent to alcohol addiction and its development, using a spectrum of individuals that range from healthy social drinkers, through people with hazardous use, to those suffering from alcohol addiction. 

Decision making can be altered in addiction, but less is known on the direct pharmacodynamic effects of alcohol intake in healthy people. Study 1 addressed decision making under the effects of moderate alcohol intoxication in healthy social drinkers using established behavioral economics tasks. The investigated processes encompassed both personal and social aspects of decision making. Within the personal domain, impulsivity and risk taking were investigated, while in the social domain, prosocial attitudes along with moral judgment were assessed. Moderate alcohol intoxication was found to impact only the social domain, leading to increased prosocial and utilitarian behaviors, but did not affect measures of impulsivity. 

Choosing alcohol over other natural rewards despite negative consequences is a central phenomenon of alcohol addiction. Two studies of this thesis investigated choice preference for alcohol compared to snack, using a cost manipulation paradigm, in light and heavy drinkers. Study 2 was a laboratory experiment whereas Study 3 was an imaging experiment for characterization of neural substrates. Cost was an important predictor of choice, as in both groups, alcohol choice was sensitive to cost in a parametric manner. This was mirrored in the brain by activity in value-based and salience regions, including orbitofrontal cortex and insula. In Study 2 we found that heavy drinkers showed generally higher alcohol choice preference and attenuated cost sensitivity. Failure to replicate this finding in Study 3, was possibly due to the artificial scanner environment. 

Craving is a key component in the cycle of addiction and a determinant of relapse, making it an important target for treatment interventions. Study 4 was a randomized sham-controlled trial using repetitive transcranial magnetic stimulation (rTMS) targeting the insula as a method to reduce craving and alcohol use in people suffering from alcohol addiction. An overall decrease in alcohol consumption and craving were seen, but did not differ between sham stimulation and rTMS targeting the insula. 

In summary, this thesis provides some insights into cognitive mechanisms related to alcohol addiction and processes that may be implicated in its development. During a moderate acute alcohol intoxication in healthy social drinkers, social decision-making is influenced, leading to increased utilitarian and altruistic behaviors. Thus, deficits in prosocial behaviors in people with alcohol addiction are unlikely to result from direct pharmacodynamic effects of alcohol, but are rather likely to reflect a selection of vulnerable individuals, consequences of the addictive process, or both. In individuals at risk of developing alcohol addiction, the sensitivity to the costs associated with choosing alcohol over an alternative reward is largely preserved, though it might be reduced compared to light, non-problem drinkers. Modulation of the insula cortex with TMS was not successful in decreasing alcohol use in individuals with alcohol addiction. 

Alcohol addiction is a psychiatric disorder characterized by a chronic relapsing trajectory and continued drinking despite negative consequences, also referred to as compulsive drinking. Craving for alcohol, a hallmark of addiction, is a predictor of relapse, and can be triggered by social stress. The mechanisms of alcohol addiction are complex, and involve environmental and genetic susceptibility factors. Social marginalization, commonly experienced by people with alcohol addiction, can promote a vicious circle of drinking and further social rejection that exacerbates the addictive state. Several studies implicate the endogenous opioid system as a link between these behaviors.

The endogenous opioid system acting through mu-opioid receptors (MORs), plays a key role in the modulation of pain and reward, but has also been proposed as a neural substrate of social attachment. Functional genetic variation in the gene encoding the MOR, OPRM1 A118G, has been reported to moderate rejection sensitivity in both primates and humans, but previous studies have been criticized due to small sample sizes. Therefore, the aim of Paper I was to test if OPRM1 A118G influenced dispositional sensitivity to rejection in an online game setting, with a sample large enough to detect small effects. However, we did not find support for this hypothesis.

The anterior cingulate cortex (ACC) and the insula are neural structures typically activated during somatic pain, but have also been reported to become activated during experimental social rejection.  This has led to the hypothesis that physical and social pain share a common alarm system, a notion consistent with high concentrations of MORs in these shared areas. However, the evidence for a social pain construct has primarily relied on fMRI studies showing task-based activations, or correlations with MOR-ligand displacement during positron emission tomography (PET) scans. These studies are merely correlational, and Paper II therefore aimed to test if MOR activation using exogenous opioids would alleviate rejection related distress in a randomized controlled trial (RCT). We found that the experimental social exclusion was associated with negative affect and the expected neural activity in the insula and the orbitofrontal cortex (OFC). However, contrary to our hypothesis, we found no influence of the prototypical MOR agonist morphine on self-reported distress or neural activity. 

Childhood maltreatment, a form of severe social stress, is a risk factor for developing addiction, but clinical assessments commonly rely on retrospective self-reports that are subject to bias. In Paper III, we examined the performance of the Childhood Trauma Questionnaire (CTQ) to detect prospectively documented childhood maltreatment in a unique cohort, that allowed us to test how Substance Use Disorder (SUD) influenced the retrospective reports. We found that the CTQ had an excellent ability to identify childhood maltreatment in individuals without SUD, but performed only slightly better than chance in people with SUD.

The insula has also been proposed to play an important role in processing alcohol craving. The insular cortex has only recently become accessible for non-invasive neuromodulation, and treatment using deep repetitive transcranial magnetic stimulation (rTMS) was reported to reduce both cigarette craving and smoking. Paper IV aimed to test if deep rTMS would be efficacious against alcohol craving and drinking. We found imaging-based evidence of neuromodulation of insula function, but despite this, we found no significant treatment effects of deep rTMS targeting this structure on alcohol craving or use.

Recent advances in brain imaging have shown that emotional and motivational states, including craving, recruit networks across the whole brain rather than being represented in isolated brain areas. The newly developed Neurobiological Craving Signature (NCS) has been shown to correlate with self-reported drug craving, an established predictor of relapse. This prompted the question whether the NCS could also predict clinical outcomes in alcohol addiction. This was evaluated in Paper V in the same patient cohort as in Paper IV. Here, we showed that the NCS was strongly correlated with self-reported craving. Most importantly, it predicted relapse and alcohol use during the three month follow-up phase.