Ketamine reduces the neural distinction between self- and other-produced affective touch: a randomized double-blind placebo-controlled study.

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.

Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial.

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.

Assessing Childhood Maltreatment Exposure in Patients Without and With a Diagnosis of Substance Use Disorder.

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.

A randomized controlled experimental medicine study of ghrelin in value-based decision making.

BACKGROUNDThe stomach-derived hormone ghrelin stimulates appetite, but the ghrelin receptor is also expressed in brain circuits involved in motivation and reward. We examined ghrelin effects on decision making beyond food or drug reward using monetary rewards.METHODSThirty participants (50% women and 50% men) underwent 2 fMRI scans while receiving i.v. ghrelin or saline in a randomized counterbalanced order.RESULTSStriatal representations of reward anticipation were unaffected by ghrelin, while activity during anticipation of losses was attenuated. Temporal discounting rates of monetary reward were lower overall in the ghrelin condition, an effect driven by women. Discounting rates were inversely correlated with neural activity in a large cluster within the left parietal lobule that included the angular gyrus. Activity in an overlapping cluster was related to behavioral choices and was suppressed by ghrelin.CONCLUSIONThis is, to our knowledge, the first human study to extend the understanding of ghrelin's significance beyond the canonical feeding domain or in relation to addictive substances. Contrary to our hypothesis, we found that ghrelin did not affect sensitivity to monetary reward anticipation, but rather resulted in attenuated loss aversion and lower discounting rates for these rewards. Ghrelin may cause a motivational shift toward caloric reward rather than globally promoting the value of reward.TRIAL REGISTRATIONEudraCT 2018-004829-82.FUNDINGSwedish Research Council (2013-07434), Marcus and Marianne Wallenberg foundation (2014.0187) and National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism Intramural Research Program.

Resilience to substance use disorder following childhood maltreatment: association with peripheral biomarkers of endocannabinoid function and neural indices of emotion regulation.

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.

Stability in Personality After Physical Trauma.

Personality trait stability may be influenced by several factors, there among different life events such as psychological trauma. However, little is known regarding trait stability after physical trauma. Therefore, our primary aim was to assess the extent of stability in personality in burn patients during the first year after injury. Eighty-four burn patients, admitted to a national burn center, were assessed with the Swedish universities Scales of Personality during acute care and 12 months postburn. Personality domain scores remained stable between acute care and 12 months postburn. On the trait level, the only change was seen in personality trait Stress Susceptibility, where burn patients' scores were lower compared with norm scores during acute care but then increased, and normalized, at 12 months postburn. To conclude, personality scores remained relatively stable during the first year after burn trauma.

Patient perception of long-term burn-specific health and congruence with the Burn Specific Health Scale-Brief.

INTRODUCTION: This qualitative study aims to explore former burn patients' perception of burn-specific health and investigate how these experiences correspond to the subscales in the Burn Specific Health Scale-Brief (BSHS-B). METHOD: Respondents were former burn patients, admitted to the Uppsala Burn Centre between 2000 and 2007. A total of 20 respondents with a Total Body Surface Area (TBSA) of 20% or larger, were approached at 10-17years after burn and interviewed using a semi-structured guide. Data was analyzed using thematic analysis. RESULTS: Despite extensive burn injuries, respondents said they led a close-to-normal life. Their descriptions validated the significance of the existing themes of BSHS-B. Additional themes of importance for health after burn were skin related problems, morphine de-escalation, the importance of work, stress and avoidance, mentality and the healthcare system. CONCLUSION: The BSHS-B alone may not be sufficient in providing a comprehensive picture of former burn patients' self-perceived health in the long-term perspective. Investigating supplementary areas reflecting former patients' sociocultural and attitudinal environment, as well as personal factors, may be of great importance.

Health-related quality of life (EQ-5D) early after injury predicts long-term pain after burn.

BACKGROUND: Chronic pain after burn can have severe physical and psychological effects on former patients years after the initial injury. Although the issue of pain after burn has gained increased attention over the past years, prospective, longitudinal studies are scarce. Our aim was to prospectively investigate consecutive burn patients for pain severity over time and to evaluate the prevalence and characteristics of post-burn pain to 2-7 years after the burn. As an additional aim, the effects of burn and individual-related factors, especially health-related Quality of Life (HRQoL), were investigated. METHOD: Sixty-seven consecutive burn patients were assessed during acute care at 3, 6, 12 and 24 months, as well as at 2-7 years post-burn. HRQoL, symptoms of post-traumatic stress disorder (PTSD) and other psychiatric disorders were investigated. During the interviews that took place 2-7 years after the injury (mean 4.6±1.9 years), current chronic post-burn pain was assessed using the Brief Pain Inventory-Short Form (BPI-SF). RESULTS: One-third of the patients still reported pain 2-7 years after the injury. Pain severity and interference with daily life were mainly mild to moderate though they were found to be associated with significantly lower HRQoL. Chronic pain after burn was associated with both burn- and individual-related factors. In logistic regression analysis HRQoL at 3 and 12 months and symptoms of PTSD at 12 months were independent factors in predicting chronic pain after burn. CONCLUSION: Pain after burn becomes a chronic burden for many former burn patients and decreases HRQoL. A novel finding in this study was that HRQoL assessed early after burn was a predictor for the development of chronic pain. This finding may help to predict future pain problems and serve as an indicator for pain preventive measures.

Prevalence and prediction of prolonged pruritus after severe burns.

Years after injury, pruritus is a common and severe problem for many burn patients. However, its characteristics and consequences are often only partially described. The authors therefore performed a prospective detailed examination of burn- and individual-related factors and considered those in relation to pruritus severity. Sixty-seven consecutive burn patients were assessed during acute care, and at 3 and 12 months postburn regarding preburn psychiatric disorders, health-related quality of life, post traumatic stress disorder, and personality traits. Postburn pruritus was subsequently assessed 2 to 7 years postburn using the Questionnaire for Pruritus Assessment. Fifty-one individuals, 76% of the participants, reported burn pruritus any time after the burn. Thirty-three individuals, 49% of the participants, reported ongoing pruritus the last 2 months. Information on the characteristics of pruritus was obtained from 32 of these individuals. Most perceived pruritus as bothersome or annoying and as present every day, 16 (50%) were considered to have severe pruritus, and 11 (34 %) scratched themselves to the point of bleeding. In logistic regressions, this was independently related to TBSA full-thickness burn and health-related quality of life at 3 months, and to TBSA full thickness burn and the personality trait impulsiveness, respectively. About half of the previous burn patients experienced ongoing pruritus on an average of 4.5 years after injury, and half of them had severe pruritus. Scratching oneself to the point of bleeding is linked both to a certain personality and to pruritus. It is suspected that many patients are left without access to the best available treatment.

Investigation into the role of gap junction modulation of intracortical connectivity in mouse neocortical brain slices.

General anesthetics are hypothesized to cause unconsciousness by interrupting communication pathways within the cerebral cortex. A correlate of this has been demonstrated in mouse neocortical slices, where anesthetics disrupt the spread of population field potential activity--resulting in a "decoupling" of activity recorded across spatial locations within the slice. In this study we investigated whether this decoupling can be explained by gap junction blockade, with a particular focus on the connexin36 (Cx36) subtype. Baseline, coupled seizure-like event (SLE) activity was recorded from two extracellular electrodes in slices perfused with no-magnesium artificial cerebrospinal fluid (aCSF). The connexin36 gap junction blocker mefloquine (25 µM) failed to decouple SLE activity in wild-type mice (median(range) decoupling rate of 0.70(0.03-3.00)%, not significantly different from controls). Slices from Cx36 knock-out mice exhibited coupled SLE activity under baseline conditions and readily decoupled when exposed to the general anesthetic etomidate. The general gap junction blocker carbenoxolone (CBX, 100 µM) strongly decoupled SLE activity compared to controls in wild-type mice (2.7(0.1-42.5) % compared to 0.03(0.0-0.5)%, p=0.0001). Taken together, the results show that Cx36 gap junction blockade does not cause decoupling of intracortical population activity, but the involvement of other gap junction subtypes cannot be ruled out.