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.

A coherent sense of self is crucial for social functioning and mental health. The N-methyl-D-aspartate antagonist ketamine induces short-term dissociative experiences and has therefore been used to model an altered state of self-perception. This randomized double-blind placebo-controlled cross-over study investigated the mechanisms for ketamine's effects on the bodily sense of self in the context of affective touch. Thirty healthy participants (15 females/15 males, age 19-39) received intravenous ketamine or placebo while performing self-touch and receiving touch by someone else during functional MRI - a previously established neural measure of tactile self-other-differentiation. Afterwards, tactile detection thresholds during self- and other-touch were assessed, as well as dissociative states, interoceptive awareness, and social touch attitudes. Compared to placebo, ketamine administration elicited dissociation and reduced neural activity associated with self-other-differentiation in the right temporoparietal cortex, which was most pronounced during other-touch. This reduction correlated with ketamine-induced reductions in interoceptive awareness. The temporoparietal cortex showed higher connectivity to somatosensory cortex and insula during other- compared to self-touch. This difference was augmented by ketamine, and correlated with dissociation strength for somatosensory cortex. These results demonstrate that disrupting the self-experience through ketamine administration affects neural activity associated with self-other-differentiation in a region involved in touch perception and social cognition, especially with regard to social touch by someone else. This process may be driven by ketamine-induced effects on top-down signaling, rendering the processing of predictable self-generated and unpredictable other-generated touch more similar. These findings provide further evidence for the intricate relationship of the bodily self with the tactile sense.

Objectives: Childhood maltreatment (CM), widely held as a risk factor for substance use disorders (SUDs), is commonly assessed using the Childhood Trauma Questionnaire (CTQ). Retrospective self-reports are, however, potentially subject to bias. We used a unique patient sample with prospectively documented CM to examine the performance of the CTQ and how this is affected by the presence of SUD.

Methods: Analysis was based on a total of 104 individuals. Subjects with prospectively recorded CM were identified from a specialized childhood trauma unit in Linköping, Sweden (n = 55; 31 with SUD, 61% females; 24 without SUD, 71% females). Clinical controls had SUD but no CM (n = 25, 48% females). Healthy controls had neither SUD nor CM (n = 24, 54% females). We analyzed the agreement between retrospective CTQ scores and prospectively documented CM by κ analysis and assessed the performance of the CTQ to identify CM exposure using receiver operating characteristic (ROC) analysis.

Results: Agreement between prospectively and retrospectively recorded CM exposure was poor for sexual abuse (36.6%, Cohen κ = 0.32, P = 0.008) and physical abuse (67.3%, κ = 0.35, P = 0.007). Overall CTQ performance was fair (ROC: area under the ROC curve = 0.78, optimal cutoff = 36.5, sensitivity = 0.65, specificity = 0.75). However, performance was excellent in the absence of SUD (area under the ROC curve = 0.93, cutoff = 32.0, sensitivity = 0.88, specificity = 0.88), but poor in participants with lifetime SUD (area under the ROC curve = 0.62, cutoff = 42.0, sensitivity = 0.60, specificity = 0.36).

Conclusions: These data support the CTQ as a tool to assess CM exposure but suggest that it may be less useful in patients with SUD.

Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicotine seeking. Here, we investigated the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) targeting the insula in alcohol addiction. Treatment-seeking alcohol-dependent patients (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition; N = 56) participated in this double-blind, sham-controlled, randomized trial. Participants received 10 Hz rTMS or sham using an H8 coil, 5 days a week for 3 weeks. Stimulation targeted insular cortex and overlaying regions bilaterally, while excluding anterior prefrontal areas. Craving and self-reported as well as biomarker-based drinking measures were collected at baseline, during treatment, and through 12 weeks. Resting-state magnetic resonance imaging (rsMRI) data were collected before and after treatment. Task-based MRI was used to probe brain correlates of reward processing, affective responses, and alcohol following completion of treatment. A marked overall decrease in craving and drinking measures was observed during treatment, but did not differ between rTMS or sham stimulation. Both groups equally increased their alcohol use following completion of treatment and through the 12-week follow-up. Analysis using seeds in the insula identified differences in resting-state connectivity between active and sham groups at completion of treatment, potentially indicating an ability of treatment to modify insula function. However, while each task robustly replicated brain responses established in the literature, no effects of rTMS were found. Collectively, this study does not support efficacy of rTMS targeting the insula in alcohol addiction. 

Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E-2 (PGE(2)) synthesis. Further, we showed that inflammation-induced PGE(2) targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE(2)-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.

Introduction Microvascular changes in the skin due to pharmacological and physiological provocations can be used as a marker for vascular function. While laser Doppler flowmetry (LDF) has been used extensively for measurement of skin microvascular responses, Laser Speckle Contrast Imaging (LSCI) and Tissue Viability Imaging (TiVi) are novel imaging techniques. TiVi measures red blood cell concentration, while LDF and LSCI measure perfusion. Therefore, the aim of this study was to compare responses to provocations in the skin using these different techniques. Method Changes in skin microcirculation were measured in healthy subjects during (1) iontophoresis of sodium nitroprusside (SNP) and noradrenaline (NA), (2) local heating and (3) post-occlusive reactive hyperemia (PORH) using LDF, LSCI and TiVi. Results Iontophoresis of SNP increased perfusion (LSCI: baseline 40.9 +/- 6.2 PU; 10-min 100 +/- 25 PU; pless than0.001) and RBC concentration (TiVi: baseline 119 +/- 18; 10-min 150 +/- 41 AU; p = 0.011). No change in perfusion (LSCI) was observed after iontophoresis of NA (baseline 38.0 +/- 4.4 PU; 10-min 38.9 +/- 5.0 PU; p = 0.64), while RBC concentration decreased (TiVi: baseline 59.6 +/- 11.8 AU; 10-min 54.4 +/- 13.3 AU; p = 0.021). Local heating increased perfusion (LDF: baseline 8.8 +/- 3.6 PU; max 112 +/- 55 PU; pless than0.001, LSCI: baseline 50.8 +/- 8.0 PU; max 151 +/- 22 PU; pless than0.001) and RBC concentration (TiVi: baseline 49.2 +/- 32.9 AU; max 99.3 +/- 28.3 AU; pless than0.001). After 5 minutes of forearm occlusion with prior exsanguination, a decrease was seen in perfusion (LDF: p = 0.027; LSCI: pless than0.001) and in RBC concentration (p = 0.045). Only LSCI showed a significant decrease in perfusion after 5 minutes of occlusion without prior exsanguination (pless than0.001). Coefficients of variation were lower for LSCI and TiVi compared to LDF for most responses. Conclusion LSCI is more sensitive than TiVi for measuring microvascular changes during SNP-induced vasodilatation and forearm occlusion. TiVi is more sensitive to noradrenaline-induced vasoconstriction. LSCI and TiVi show lower inter-subject variability than LDF. These findings are important to consider when choosing measurement techniques for studying skin microvascular responses.