| 1. |
- Karlsson, Hanna, 1989-
(författare)
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From social drinking to alcohol addiction : Decision making and its neural substrates along a spectrum from social drinking to alcohol addiction
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Löfberg, Andreas, 1987-, et al.
(författare)
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Assessing Childhood Maltreatment Exposure in Patients Without and With a Diagnosis of Substance Use Disorder
- 2023
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Ingår i: Journal of addiction medicine. - : Wolters Kluwer. - 1932-0620 .- 1935-3227. ; 17:3, s. 263-270
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Middleton, Steven J, et al.
(författare)
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Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.
- 2022
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 145:10, s. 3637-3653
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Tidskriftsartikel (refereegranskat)abstract
- Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial EMG (n = 3 CIP participants and n = 8 healthy controls) we have found that these patients also have abnormalities in the encoding of affective touch which is mediated by the specialised afferents; C-low threshold mechanoreceptors (C-LTMRs). In the mouse we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.
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| 4. |
- Perini, Irene, 1983-, et al.
(författare)
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Repetitive transcranial magnetic stimulation targeting the insular cortex for reduction of heavy drinking in treatment-seeking alcohol-dependent subjects: a randomized controlled trial
- 2020
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Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 45:5, s. 842-850
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Perini, Irene, 1983-, et al.
(författare)
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Resilience to substance use disorder following childhood maltreatment: association with peripheral biomarkers of endocannabinoid function and neural indices of emotion regulation
- 2023
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Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; :6, s. 2563-2571
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Tidskriftsartikel (refereegranskat)abstract
- Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure.
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| 6. |
- Perini, Irene, 1983-, et al.
(författare)
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Social Acts and Anticipation of Social Feedback
- 2022
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Ingår i: Neuroscience of Social Stress. - Cham : Springer. - 9783031042560 - 9783031042553 ; , s. 393-416
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Socialization happens so regularly in humans that it can be perceived as an effortless activity. However, it reflects a sophisticated behavior, pervaded by anticipation and emotion. The fast-paced social interplay, strongly mediated by facial expressions, can be considered one of the most frequent high-order motor acts within the human behavioral repertoire. The ability to adequately process social feedback is critical for appropriate socialization and affects well-being. The social difficulties often observed in psychiatric patients highlight the link between mental health and successful socialization and the importance of characterizing the behavioral and neural mechanisms of social interaction. This chapter will present some cross-species evidence on the cortical regions engaged during social interactions including facial expressions, and the impact of induced or perceived social stress on the experience of social interactions.
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| 7. |
- Pietrzak, Michal, 1987-, et al.
(författare)
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Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial
- 2024
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Ingår i: Neuropsychopharmacology. - : Springer Science+Business Media B.V.. - 0893-133X .- 1740-634X. ; 49, s. 1042-1049
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Tidskriftsartikel (refereegranskat)abstract
- The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants' task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = -2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values >= 4.21, p-values <= 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.
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| 8. |
- Sangchooli, Arshiya, et al.
(författare)
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Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity
- 2024
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Ingår i: JAMA psychiatry. - : AMER MEDICAL ASSOC. - 2168-6238 .- 2168-622X.
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Forskningsöversikt (refereegranskat)abstract
- Importance In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.
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