Markus Heilig's research while affiliated with Linköping University and other places

Publications (490)

Article
Full-text available
Background There are currently no approved medications for impaired social cognition and function, core symptoms of autism spectrum disorder. We describe marked improvement of these symptoms with long-term low-dose administration of the partial µ-opioid agonist buprenorphine. We discuss these observations in the context of a role for endogenous opi...
Article
Background : Depressive disorders (DD) and alcohol use disorders (AUD) frequently co-occur. They are key to understanding the current increases in “deaths of despair” among individuals with lower socioeconomic status (SES). The aim of this study was to assess the prospective bidirectional associations between AUD and DD, as well as the effect of SE...
Article
Full-text available
The endocannabinoid (eCB) system is one the most ubiquitous signaling systems of the brain and offers a rich pharmacology including multiple druggable targets. Preclinical research shows that eCB activity influences functional connectivity between the prefrontal cortex and amygdala, thereby influences an organism’s ability to cope with threats and...
Article
Full-text available
Childhood maltreatment is considered a risk factor for substance use disorders (SUD), but this is largely based on retrospective self-reports that are subject to recall bias, designs that do not control for familial confounding, or both. The specific contribution of childhood maltreatment to SUD risk thus remains unclear. Here, we evaluated this co...
Article
Full-text available
An impairment of social communication is a core symptom of autism-spectrum disorder (ASD). Affective touch is an important means of social interaction, and C-Tactile (CT) afferents are thought to play a key role in the peripheral detection and encoding of these stimuli. Exploring the neural and behavioral mechanisms for processing CT-optimal touch...
Article
Full-text available
The GABAB receptor (GABABR) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alco...
Article
Full-text available
The view that substance addiction is a brain disease, although widely accepted in the neuroscience community, has become subject to acerbic criticism in recent years. These criticisms state that the brain disease view is deterministic, fails to account for heterogeneity in remission and recovery, places too much emphasis on a compulsive dimension o...
Article
Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal s...
Article
Full-text available
Exposure to traumatic events during childhood increases the risk of adult psychopathology, including anxiety, depression, alcohol use disorders and their co-morbidity. Early life trauma also results in increased symptom complexity, treatment resistance and poor treatment outcomes. The purpose of this study was to establish a novel rodent model of a...
Article
Full-text available
Dual-process theory is a widely utilized modelling tool in the behavioral sciences. It conceptualizes decision-making as an interaction between two types of cognitive processes, some of them fast and intuitive, others slow and reflective. We make a novel contribution to this literature by exploring differences between adults with clinically diagnos...
Article
Critical features of human addiction are increasingly being incorporated into complementary animal models, including escalation of drug intake, punished drug seeking and taking, intermittent drug access, choice between drug and non-drug rewards, and assessment of individual differences based on criteria in the fourth edition of the Diagnostic and S...
Article
Full-text available
RationaleProinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therape...
Article
Full-text available
Background and purpose: Alcohol and nicotine use disorder are commonly comorbid. Both alcohol and nicotine can activate opioid systems in reward-related brain regions, leading to adaptive changes in opioid signaling upon chronic exposure. The potential role of these adaptations for comorbidity is presently unknown. Here, we therefore examined the...
Article
Full-text available
Introduction Differentiation between self-produced tactile stimuli and touch by others is necessary for social interactions and for a coherent concept of “self”. In attention-deficit-hyperactivity-disorder (ADHD), tactile hypersensitivity and social cognition problems are part of the symptomatology, but pathophysiological mechanisms are largely unk...
Article
Full-text available
Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated leve...
Article
In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it...
Article
Full-text available
Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-51...
Article
Full-text available
The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whet...
Article
Full-text available
Excessive alcohol use is the cause of an ongoing public health crisis, and accounts for ~5% of global disease burden. A minority of people with recreational alcohol use develop alcohol addiction (hereafter equated with “alcohol dependence” or simply “alcoholism”), a condition characterized by a systematically biased choice preference for alcohol at...
Article
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 Disorde...
Article
Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we...
Article
Full-text available
Objectives: The Addiction Severity Index (ASI) is a standardized interview used to assess problems associated with substance use. Although widely used, the time required for the interview remains an obstacle to its acceptance in many clinical settings. We examined if a self-administered questionnaire based on the composite score (CS) items, the ASI...
Article
Full-text available
PPARγ, an isoform of Peroxisome Proliferator-Activated Receptors is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. Neuroanatomical data indicate PPARγ localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-a...
Article
Full-text available
The latest revision of the International Classification of Diseases (ICD‐11) is slated for publication in mid‐2019 and will include a revised definition for alcohol use disorders (AUDs) and, more specifically, for alcohol dependence and the “harmful patterns of alcohol use.” In a recent issue, Saunders and colleagues (Saunders et al., 2019) reviewe...
Article
Alcohol use disorders consist of disorders characterised by compulsive heavy alcohol use and loss of control over alcohol intake. Alcohol use disorders are some of the most prevalent mental disorders globally, especially in high-income and upper-middle-income countries; and are associated with high mortality and burden of disease, mainly due to med...
Article
Full-text available
Epigenetic enzymes oversee long-term changes in gene expression by integrating genetic and environmental cues. While there are hundreds of enzymes that control histone and DNA modifications, their potential roles in substance abuse and alcohol dependence remain underexplored. A few recent studies have suggested that epigenetic processes could under...
Article
Background: Posttraumatic stress disorder, an area of large unmet medical needs, is characterized by persistence of fear memories and maladaptive stress responses. In rodents, elevation of the endocannabinoid anandamide due to inhibition of fatty acid amide hydrolase (FAAH) facilitates fear extinction and protects against the anxiogenic effects of...
Article
Full-text available
Background: Interpersonal stress and perceived rejection have been clinically observed as common triggers of nonsuicidal self-injury (NSSI), with self-injury behavior regulating both affective and social experiences. We investigated whether the subjective interpretation of social interaction in a simulated online environment might be biased in the...
Article
Given previous findings from animal studies and small-scale studies in humans, variation in the μ-opioid receptor gene (OPRM1) has been proposed as a strong biological candidate for moderating sensitivity to social rejection. Using a substantially larger sample (N = 490) than previous studies, a prospective genotyping strategy, and preregistered an...
Article
Genetic factors significantly contribute to the risk for developing alcoholism. To study these factors and other associated phenotypes, rodent lines have been developed using selective breeding for high alcohol preference. One of these models, the alcohol preferring (P) rat, has been used in hundreds of preclinical studies over the last few decades...
Article
Full-text available
Stress is an inevitable part of life that can profoundly impact social and emotional functioning, contributing to the development of psychiatric disease. One key component of emotion and social processing is facial expressions, which humans can readily detect and react to even without conscious awareness. Facial expressions have been the focus of p...
Article
Repetitive transcranial magnetic stimulation (rTMS) is an evidence-based treatment option for major depressive disorder (MDD). However, comparisons of efficacy between the two FDA-approved protocols of rTMS modalities are lacking. The aim of this industry-independent, randomized-controlled, single-blind trial was to evaluate clinical outcome of the...
Article
"Affective" touch is believed to be processed in a manner distinct from discriminatory touch and to involve activation of C-tactile (CT) afferent fibers. Touch that optimally activates CT fibers is consistently rated as hedonically pleasant. Patient groups with impaired social-emotional functioning also show disordered affective touch ratings. Howe...
Article
Full-text available
Background: Preclinical and human positron emission tomography studies have produced inconsistent results regarding the effects of opioids on mesolimbic dopamine (DA). Here, we quantify striatal DA release (measured by [11C]raclopride displacement) in response to an intravenous infusion of morphine, and its relationship with morphine-induced subje...
Article
Full-text available
Background/objectives: Ghrelin, a stomach-derived hormone implicated in numerous behaviors including feeding, reward, stress, and addictive behaviors, acts by binding to the growth hormone secretagogue receptor (GHSR). Here, we present the development, verification, and initial characterization of a novel GHSR knockout (KO) Wistar rat model create...
Article
Full-text available
Differentiation between self-produced tactile stimuli and touch by others is necessary for social interactions and for a coherent concept of “self.” The mechanisms underlying this distinction are unknown. Here, we investigated the distinction between self- and other-produced light touch in healthy volunteers using three different approaches: fMRI,...
Article
Full-text available
Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striata...
Article
The epidemic of addiction and overdose is real. Addiction among pain patients accounts for only a small proportion but a large number. Scientific opinion leaders can be most effective on two fronts, each relatively low-tech: dissemination and oversight of empirically established treatments, and promulgation of social-science-based strategies for po...
Article
Full-text available
Modulating the function of the insular cortex could be a novel therapeutic strategy to treat addiction to a variety of drugs of abuse as this region has been implicated in mediating drug reward and addictive processes. The recent advent of the H-coil has permitted the targeting of deeper brain structures which was not previously feasible. The goal...
Article
Objective To evaluate the safety and efficacy of low‐frequency, inhibitory, deep rTMS with a novel H‐coil specifically designed to stimulate the insula. Methods In a randomized, crossover order, 16 healthy volunteers underwent two sessions (sham; active) of 1 Hz repetitive TMS at an intensity of 120% of individual motor threshold, over the right a...
Article
Full-text available
Background: Preliminary evidence suggested that the PPARγ agonist pioglitazone reduces opioid-withdrawal symptoms, possibly by inhibiting increases in proinflammatory cytokines. Methods: A randomized, placebo-controlled clinical trial was conducted utilizing two different study designs (entirely outpatient, and a combination of inpatient and out...
Article
Background: Compulsive alcohol use, the tendency to continue alcohol seeking and taking despite negative consequences, is a hallmark of alcohol use disorder. Preclinical rodent studies have suggested a role for the medial prefrontal cortex, anterior insula, and nucleus accumbens in compulsive alcohol seeking. It is presently unknown whether these...
Article
Touch plays a central role in interpersonal behavior, especially in its capacity to convey-and induce- changes in affect. Previous research has established that slow, caress-like stroking over the skin elicits positive subjective affective responses, with higher ratings of "pleasantness" compared to a faster-moving touch stimulus. Ratings of pleasa...
Article
Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which ~15% of outbred rats chose alcohol over a high-value reward. These animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression o...
Article
We have previously demonstrated that the neurokinin-1 receptor (NK1R) is upregulated in the central nucleus of the amygdala of alcohol preferring (P) rats and that this receptor mediates escalated alcohol consumption in this strain. However, it is unclear if non-genetic models of escalated consumption are also mediated by NK1R signaling, and if so,...
Article
Full-text available
The human neural correlates of social rejection have attracted significant research interest, but remain subject to vigorous debate. Specifically, it has been proposed that a matrix of brain regions overlapping with the classical pain matrix, and including the dorsal anterior cingulate cortex (dACC) and the anterior insular cortex (AI) is critical...
Article
Background: The gene encoding Phosphatidylinositol-4-Phosphate 5-Kinase (PIP5K1C) has been recently implicated in pain regulation. Interestingly, a recent cross-tissue and cross-phenotypic epigenetic analysis identified the same gene in alcohol use disorder (AUD). Given the high comorbidity between AUD and chronic pain, we hypothesized that geneti...
Article
Full-text available
The risk factors for developing alcohol addiction include impulsivity, high sensitivity to the rewarding action of ethanol, and low sensitivity to its sedative and intoxicating effects. Genetic variation in GABAAreceptor subunits, including the ɣ2 subunit (Gabrg2), affects the risk for developing alcoholism. Alcohol directly potentiates GABAArecept...
Article
Full-text available
Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a ca...
Article
Full-text available
Drug cues, or conditioned responses to stimuli paired with drugs, are widely believed to promote drug use. The acquisition of these conditioned responses has been well characterized in laboratory animals: neutral stimuli paired with drugs elicit conditioned responses resembling the motivational and incentive properties of the drug itself. However,...
Article
Full-text available
Aims: Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown....