Introduction Olfaction has an important role in physiological and affective processes, as well as the potential to have profound effects on activities such as sleep and learning. We investigated two commercially manufactured odors ("Deep Sleep" and "Oriental," from This Works) purported to promote sleep, compared with control odor, where we aimed to explore whether neural and behavioral differences existed after odor inhalation. Methods In a neuroimaging study, 30 healthy participants were exposed to the odors via an olfactometer during functional magnetic resonance imaging (fMRI). In a further behavioral study using 12 chronic insomniacs, we investigated whether the commercial odors showed effects on sleep during a double-blind, randomized home evaluation. Results In the neuroimaging, the odors were related to activation of olfactory-relevant areas, such as the orbitofrontal cortex, and we found positive connectivity between the piriform cortex and the hippocampus, amygdala, insula, and middle cingulate cortex. Deep Sleep specifically activated the superior temporal gyrus, whereas Oriental activated the caudate. Further, these commercial odors showed some beneficial impact on sleep. Conclusions The perceptual and neural impacts of the commercial odors showed that olfactory stimulation can potentially aid sleep and modify affective processes in a number of ways. Implications The present work opens up opportunities for further investigations into how different odors may lead to specific behavioral and physiological modifications, such as their impact on sleep and well-being, which may provide non-pharmacological alternative approaches.

In homeostasis, somatosensory C fibre afferents are hypothesised to mediate input to the brain about interactions with external stimuli and sympathetic efference provides the output that regulates bodily functions. We aimed to test this hypothesis and whether different types of innocuous somatosensory input have differential effects. Healthy volunteers performed a muscle fatigue (hand-grip) task to exhaustion, which produces increased muscle sympathetic nerve activity (MSNA), as measured through microneurography. Participants completed the muscle fatigue task without concurrent cutaneous sensory stimulation (control) or we applied skin warming (heat pack) as a C fibre stimulation, slow brush stroking as C and A beta fibre stimulation, or vibration as A beta fibre stimulation, to the participants forearm. We also measured heart rate, the duration of the hand-grip task, and ratings of pain at the end of the task. Concurrent skin warming showed increased MSNA compared to the other conditions. Tactile stimuli (brushing, vibration) were not significantly different to the control (no intervention) condition. Warming increased the pain from the muscle contraction, whereas the tactile stimuli did not. We interpret the effect of warming on MSNA as providing relevant afferent information during muscle contraction, which needed to be counteracted via vasoconstriction to maintain homeostasis. Brushing and vibration were less homeostatically relevant stimuli for the muscle contraction and hence had no significant effect. The findings add sensory specificity to our current understanding of homeostatic regulation through somatosensory afferent and sympathetic efferent pathways.

Background The Swedish national quality register for electroconvulsive therapy (Q-ECT) contains data on patients receiving treatment with electroconvulsive therapy (ECT) in Sweden. Aim This study determined the validity of diagnoses, treatment dates, and rating scales in the Q-ECT by investigating the degree of accordance between data from the Q-ECT and patient records. Materials and methods From January 2016 to December 2017, 200 treatment series were randomly selected from the Q-ECT. The corresponding patient records were requested from the treating hospitals. Data on the indicative diagnosis, dates for the first and the last ECT session, and rating scales were compared between the Q-ECT and patient records using (i) a strict and (ii) a liberal method of assessment. Using the liberal method, each variable was assessed as accordant if it belonged to the same diagnosis group, or if the dates differed by less than 1 week, or ratings differed by only 1 point on the Clinical Global Impression Scale (CGI- S), or no more than 3 points on the Montgomery angstrom sberg Depression Rating Scale between the Q-ECT and the patient record. Results A total of 179 patient records were received. The strict method of assessment showed an accordance of 89% or higher for all studied variables. The liberal method showed an accordance of 95% or higher. Conclusions We conclude that data on the studied variables in the Q-ECT have high validity. However, limited use of some rating scales makes the results uncertain. Measures can be taken to further improve the data quality.

The 2030 Agenda for Sustainable Development and its seventeen Sustainable Development Goals were adopted by the United Nations General Assembly in 2015. It is a bold agenda for global social, environmental and economic development, with human health as a central theme. Even though substantial improvements in health have been achieved during the last decades, every year over 5 million children die, mostly from preventable causes, and 300 000 women die in conjunction with childbirth. Premature deaths from non-communicable diseases are increasing, and our ability to treat infections is under threat through widespread anti-microbial resistance. Climate change is recognized as the biggest threat to health in our time. When the world now starts to plan for how society and our health systems should be reorganized after the COVID-19 pandemic the 2030 Agenda could and should play a central role. In this context, Agenda 2030 provides an ambitious roadmap for development, with its emphasis on collaboration across borders and disciplines. The agenda is achievable but reaching its goals will require strong commitment at all levels and societal change on a large scale.

Background: The COVID-19 pandemic has been associated with various negative psychological consequences. This is a challenge for the society as regular psychological services cannot be offered to the same extent as before the pandemic. In addition to the requirement of social distancing, there is a need to adjust psychological treatment components like exposure to avoid increasing the spread of the infection. Internet-delivered cognitive behavior therapy (ICBT) has an established evidence base for a range of psychiatric problems and has been suggested as one possible approach to deal with the situation. This study aimed to conduct a randomized controlled pilot trial during the summer of 2020 with a broad focus on psychological distress and a treatment approach that tailors the intervention based on symptom profile and preferences.

Methods: Following the advertisement and interview, we included 52 participants with elevated levels of psychological distress. They were randomly allocated to either a 7-week-long individually tailored ICBT (n = 26) or a wait-list control condition (n = 26). Measures of depression and quality of life were used as primary outcomes. We also included secondary outcome measures of anxiety, insomnia, trauma, stress, anger, and alcohol use. For screening, we used the CoRonavIruS Health Impact Survey (CRISIS).

Results: Overall moderate to large between-group effects were found at post-treatment in favor of the treatment on measures of both depression [Beck Depression Inventory (BDI); Cohens d = 0.63; Patient Health Questionnaire (PHQ-9): d = 0.62] and anxiety [Generalized Anxiety Disorder-7-item scale (GAD-7); d = 0.82]. This was also observed for stress symptoms [Perceived Stress Scale (PSS-14); d = 1.04]. No effects were seen on measures of quality of life, insomnia, symptoms of post-traumatic stress, and anger. There was an effect on alcohol use [Alcohol Use Disorder Identification Test (AUDIT); d = 0.54], which was not of clinical relevance.

Conclusion: Individually tailored ICBT shows initial promise as a way to reduce psychological problems in association with the COVID-19 pandemic. A possible limitation was that the trial was conducted when the effects of the pandemic were decreasing and when fewer people were affected by the restrictions (e.g., the summer of 2020).

Even if much is known regarding the effects of internet-delivered cognitive behaviour therapy (ICBT) for depression there are several topics that have not been studied. In this factorial design trial with 197 participants we investigated if clients in ICBT could select treatment modules themselves based on a selection of 15 tailored treatment modules developed for use in ICBT for depression. We contrasted this against clinician-tailored module selection. We also investigated if support on demand (initiated by the client) could work as well as scheduled support. Finally, we tested if clients that were mentioned in supervision would improve more than clients not mentioned (with the exception of acute cases). The treatment period lasted for 10 weeks, and we measured effects at post-treatment and two-year follow-up. Measures of depression and secondary outcomes were collected at pre-treatment, post-treatment and two-year follow-up. Overall, within-group effects were large across con-ditions (e.g., d = 1.73 on the BDI-II). We also found a small but significant difference in favour of self-tailored treatment over clinician-tailored (d = 0.26). Within-group effects for the secondary measures were all moderate to large including a test of knowledge about CBT. The other two contrasts "support on demand" and "supervision" yielded mostly non-significant differences, with the exception of a larger dropout rate in the support on demand condition. There were few negative effects (2.2%). Effects were largely maintained at a two-year follow-up. We conclude that clients can choose treatment modules and that support on demand may work. The role of su-pervision is not yet clear as advice can be transferred across clients.

BackgroundNonsuicidal self-injury (NSSI) is common in adolescents. Emotion dysregulation has been identified as a core mechanism in the development and maintenance of NSSI and it is therefore an important target when addressing NSSI. The pathogenic connection between different kinds of childhood abuse, difficulties in emotion regulation and NSSI needs further investigation. The objective of this study was to examine whether difficulties with emotion regulation and trauma symptoms, separately and together, mediate the relationships between sexual, physical and emotional abuse and NSSI. MethodCross-sectional data was collected from 3,169 adolescent high-school students aged 16-19 years (M = 18.12, SD = 0.45). Data from self-reported experiences of childhood abuse, current difficulties with emotion regulation (measured with the Difficulties with Emotion Regulation Scale, DERS-16) and trauma symptoms (measured with the Trauma Symptom Checklist for Children, TSCC), and NSSI were collected. Structural Equation Modeling (SEM) was used to test the proposed relationships between variables. ResultsThe prevalence of life-time NSSI was 27.4%. Prevalence of reported childhood abuse was 9.2, 17.5, and 18.0% for sexual, physical, and emotional abuse, respectively. Childhood abuse, difficulties with emotion regulation and trauma symptoms exhibited significant positive associations with NSSI in adolescents. Emotional dysregulation and trauma symptoms were both found to mediate the relationship between childhood abuse and NSSI. Latent variable models were found to fit data well. ConclusionResults indicate that increased levels of emotional dysregulation and trauma symptoms in relation to childhood abuse contribute to the increased risk of NSSI. Further, results point to some aspects of emotional dysregulation and trauma symptoms being more important in this regard. Clinical implications are discussed.

OBJECTIVE To evaluate HbA(1c) followed from diagnosis, as a predictor of severe microvascular complications (i.e., proliferative diabetic retinopathy [PDR] and nephropathy [macroalbuminuria]). RESEARCH DESIGN AND METHODS In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age from 1983 to 1987 in southeast Sweden were followed from diagnosis until 2019. Long-term weighted mean HbA(1c) (wHbA(1c)) was calculated by integrating the area under all HbA(1c) values. Complications were analyzed in relation to wHbA(1c) categorized into five levels. RESULTS After 32 years, 9% had no retinopathy, 64% non-PDR, and 27% PDR, and 83% had no microalbuminuria, 9% microalbuminuria, and 8% macroalbuminuria. Patients with near-normal wHbA(1c) did not develop PDR or macroalbuminuria. The lowest wHbA(1c) values associated with development of PDR and nephropathy (macroalbuminuria) were 7.3% (56 mmol/mol) and 8.1% (65 mmol/mol), respectively. The prevalence of PDR and macroalbuminuria increased with increasing wHbA(1c), being 74% and 44% in the highest category, wHbA(1c) >9.5% (>80 mmol/mol). In comparison with the follow-up done after 20-24 years duration, the prevalence of PDR had increased from 14 to 27% and macroalbuminuria from 4 to 8%, and both appeared at lower wHbA(1c) values. CONCLUSIONS wHbA(1c) followed from diagnosis is a very strong biomarker for PDR and nephropathy, the prevalence of both still increasing 32 years after diagnosis. To avoid PDR and macroalbuminuria in patients with type 1 diabetes, an HbA(1c) <7.0% (53 mmol/mol) and as normal as possible should be recommended when achievable without severe hypoglycemia and with good quality of life.

BackgroundLimited time management skills cause problems in daily life for people with mild intellectual disability (ID) and "Lets Get Organized" (LGO) is a promising manual-based occupational therapy group intervention aiming to support management skills.Aims/ObjectivesTo evaluate the applicability of the Swedish version of LGO-S by i) exploring enhancements in time management skills, satisfaction with daily occupations, and aspects of executive functioning in people with time-management difficulties and mild ID, and ii) describing clinical experiences of using the LGO-S for people with mild ID.Material and methodsTwenty-one adults with mild ID were included. Data were collected pre-/post-intervention and at 3- and 12-month follow-ups with: Swedish version of Assessment of Time Management Skills (ATMS-S), Satisfaction with Daily Occupation (SDO-13), and Weekly Calendar Planning Activity (WCPA-SE). There were few follow-up participants (n = 6-9).ResultsSignificant change in time management skills that maintained at 12-months follow-ups. Significant increase in regulation of emotions at 12-month follow-up. Results at 12-months follow-up indicated sustainability in outcomes as measured by ATMS-S. A non-significant positive trend was observed in other outcomes between pre- and post-intervention.Conclusions and significanceLGO-S seems applicable for improving skills in time management, organisation and planning also for people with mild ID.

Humans receive a constant stream of input that potentially influence their affective experience. Despite intensive research on affect, it is still largely unknown how various sources of information are integrated into the single, unified affective features that accompany consciousness. Here, we aimed to investigate how a stream of evocative input we receive is dynamically represented in self-reported affect. In 4 experiments, participants viewed a number of sequentially presented images and reported their momentary affective experience on valence and arousal scales. The number and duration of images in a trial varied across studies. In Study 4, we also measured participants physiological responses while they viewed images. We formulated and compared several models with respect to their capacity to predict self-reported affect based on normative image ratings, physiological measurements, and prior affective experience (measured in the previous trial). Our data best supported a model incorporating a temporally sensitive averaging mechanism for affective integration that assigns higher weights to effectively more potent and recently represented stimuli. Crucially, affective averaging of sensory information and prior affect accounted for distinct contributions to currently experienced affect. Taken together, the current study provides evidence that prior affect and integrated affective impact of stimuli partly shape currently experienced affect.

Affect fluctuates in a moment-to-moment fashion, reflecting the continuous relationship between the individual and the environment. Despite substantial research, there remain important open questions regarding how a stream of sensory input is dynamically represented in experienced affect. Here, approaching affect as a temporally dependent process, we show that momentary affect is shaped by a combination of the affective impact of stimuli (i.e., visual images for the current studies) and previously experienced affect. We also found that this temporal dependency is influenced by uncertainty of the affective context. Participants in each trial viewed sequentially presented images and subsequently reported their affective experience, which was modeled based on images normative affect ratings and participants previously reported affect. Study 1 showed that self-reported valence and arousal in a given trial is partly shaped by the affective impact of the given images and previously experienced affect. In Study 2, we manipulated context uncertainty by controlling occurrence probabilities for normatively pleasant and unpleasant images in separate blocks. Increasing context uncertainty (i.e., random occurrence of pleasant and unpleasant images) was associated with increased negative affect. In addition, the relative contribution of the most recent image to experienced pleasantness increased with increasing context uncertainty. Taken together, these findings provide clear behavioral evidence that momentary affect is a temporally dependent and continuous process, which reflects the affective impact of recent input variables and the previous internal state, and that this process is sensitive to the affective context and its uncertainty.

Aims: The effects of alcohol on gamma-aminobutyric acid (GABA) transmission are key for the development and maintenance of alcohol use disorder (AUD). Previous research consistently indicates that GABA(B) receptor agonists such as baclofen can attenuate addiction-related behaviors in preclinical models of AUD. More importantly, baclofen has also shown promise in clinical studies, particularly in severely alcohol-dependent patients. However, despite this promise, other clinical studies have not confirmed its efficacy and chiefly, larger clinical trials have not been conducted. Therefore, with the exception of France, baclofen is not approved for the treatment of AUD in any other country. Furthermore, it is also important to keep in mind that some patients treated with baclofen may experience important side-effects, including sedation, drowsiness and sleepiness. Methods: This short review will first discuss the history of baclofen for AUD treatment. We will then summarize preclinical behavioral results that have investigated the efficacy of GABA(B) PAMs for addiction treatment, with a special focus on our recent work that investigated the effects of ADX71441, a novel GABA(B) PAM, on several alcohol-related behaviors in rats that model important aspects of human AUD. Finally, in light of the recent criticism about the translational value of animal models of addiction, the specific translational potential of our work and of other preclinical studies that have unanimously reported the efficacy of GABA(B) PAMs to attenuate multiple alcohol-related behaviors will be discussed. Results: Positive allosteric modulators (PAMs) of the GABA(B) receptor offer an attractive alternative approach to baclofen and have the potential to achieve mechanistic and therapeutic effects similar to GABA(B) agonists, while avoiding the tolerance and toxicity issues associated with baclofen. To date, all preclinical behavioral results have invariably shown the efficacy of GABA(B) PAMs for addiction treatment. Conclusions: Preclinical studies indicate that GABA(B) PAMs have a higher therapeutic index than orthosteric agonists, at least in terms of mitigating the sedative effects of GABA(B) agonism. This predicts that GABA(B) PAMs have a high translational potential in humans and merit being tested clinically, in particular in patients with severe AUD.

Animal models of substance use disorders have been criticized for their limited translation. One important factor behind seeking and taking that has so far been largely overlooked is the availability of alternative non-drug rewards. We recently reported that only about 15% of outbred Wistar rats will choose alcohol over a sweet solution of saccharin. It was also shown using a novel operant model of choice of drugs over social rewards that social interaction consistently attenuates self-administration and incubation of craving for stimulants and opioids. Whether this is also true for alcohol and choice of alcohol over a sweet reward translates to social rewards is currently unknown. We therefore evaluated choice between alcohol and a social reward in different experimental settings in both male and female Wistar rats. We found, in contrast to prior work that employed discrete choice of drugs vs. social reward, that rats almost exclusively prefer alcohol over social interaction, irrespective of the nature of the social partner (cagemate vs. novel rat), the length of interaction, housing conditions and sex. Alcohol choice was reduced when the response requirement for alcohol was increased. However, rats persisted in choosing alcohol, even when the effort required to obtain it was 10-16 times higher (for females and males respectively) than the one for the social reward. Altogether, these results indicate that the social choice model may not generalize to alcohol, pointing to the possibility that specific interactions between alcohol and social reward, not seen when a sweet solution is used as an alternative to the drug, may play a crucial role in alcohol vs. social choice experiments.

Rationale Identifying the long-term neurocognitive implications of opioid addiction may further our understanding of the compulsive nature of this brain disorder. The aim of this study was to examine the effects of paternal adolescent opiate exposure on cognitive performance (visual attention, impulsivity, and compulsivity) in the next generation. Methods Male Wistar rats received escalating doses of morphine (2.5-25 mg/kg, s.c.) or saline for 10 days during adolescence (P30-39). In adulthood (P70-80), these rats were allowed to mate with drug-naive females. Male offspring from morphine- and saline-exposed sires, once in adulthood, were trained and tested in the 5-choice serial reaction time test (5-CSRTT) to evaluate their cognitive abilities under baseline, drug-free conditions as well as following acute (1, 3, 5 mg/kg morphine) and subchronic morphine (5 mg/kg morphine for 5 days) treatment. Behavioral effects of the opioid receptor antagonist naloxone were also assessed. Results Morphine-sired offspring exhibited delayed learning when the shortest stimulus duration (1 s) was introduced, i.e., when cognitive load was highest. These subjects also exhibited a reduced ability to exert inhibitory control, as reflected by increased premature and perseverative responding under drug-free baseline conditions in comparison to saline-sired rats. These impairments could not be reversed by administration of naloxone. Moreover, impulsive behavior was further enhanced in morphine-sired rats following acute and subchronic morphine treatment. Conclusion Paternal opiate exposure during adolescence was found to primarily impair inhibitory control in male progeny. These results further our understanding of the long-term costs and risk of opioid abuse, extending across generations.

Irritable bowel syndrome (IBS) is a chronic pain disorder characterized by disturbed interactions between the gut and the brain with depression as a common comorbidity. In both IBS and depression, structural brain alterations of the insular cortices, key structures for pain processing and interoception, have been demonstrated but the specificity of these findings remains unclear. We compared the gray matter volume (GMV) of insular cortex (IC) subregions in IBS women and healthy controls (HC) and examined relations to gastrointestinal (GI) symptoms and glutamate + glutamine (Glx) concentrations. We further analyzed GMV of IC subregions in women with major depression (MDD) compared to HC and addressed possible differences between depression, IBS, IBS with depression and HC.

BACKGROUND: Alcohol addiction is characterized by persistent neuroadaptations in brain structures involved in motivation, emotion, and decision making, including the medial prefrontal cortex, the nucleus accumbens, and the amygdala. We previously reported that induction of alcohol dependence was associated with long-term changes in the expression of genes involved in neurotransmitter release. Specifically, Syt1, which plays a key role in neurotransmitter release and neuronal functions, was downregulated. Here, we therefore examined the role of Syt1 in alcohol-associated behaviors in rats. METHODS: We evaluated the effect of Syt1 downregulation using an adeno-associated virus (AAV) containing a short hairpin RNA against Syt1. Cre-dependent Syt1 was also used in combination with an rAAV2 retro-Cre virus to assess circuit-specific effects of Syt1 knockdown (KD). RESULTS: Alcohol-induced downregulation of Syt1 is specific to the prelimbic cortex (PL), and KD of Syt1 in the PL resulted in escalated alcohol consumption, increased motivation to consume alcohol, and increased alcohol drinking despite negative consequences ("compulsivity"). Syt1 KD in the PL altered the excitation/inhibition balance in the basolateral amygdala, while the nucleus accumbens core was unaffected. Accordingly, a projection-specific Syt1 KD in the PL-basolateral amygdala projection was sufficient to increase compulsive alcohol drinking, while a KD of Syt1 restricted to PL-nucleus accumbens core projecting neurons had no effect on tested alcohol-related behaviors. CONCLUSIONS: Together, these data suggest that dysregulation of Syt1 is an important mechanism in long-term neuroadaptations observed after a history of alcohol dependence, and that Syt1 regulates alcohol-related behaviors in part by affecting a PL-basolateral amygdala brain circuit.

Alcohol use is a leading cause of death and disease worldwide. A large part of this disease burden is associated with alcohol use disorder (AUD), a diagnostic category characterized by excessive use in spite of negative consequences ("compulsive use"), a loss of control over intake, and choice of alcohol over natural rewards. These behavioral symptoms are believed to reflect the emergence of persistent neuroadaptations in key brain regions that exert control over motivated behavior. A major challenge to addressing the treatment needs of patients with AUD is the high prevalence of co-occurring psychiatric disorders, of which anxiety disorders are the most common. Both AUD and anxiety disorders are characterized by broad changes in gene expression within brain regions that include the prelimbic cortex (PL) and the amygdala complex. Although the risk for AUD has a substantial genetic component, heavy alcohol use and stress also contribute to disease risk. 

Our lab previously identified DNA hypermethylation as a mechanism behind alcohol-induced downregulation of prelimbic Syt1 and Prdm2. In a subsequent study, our lab demonstrated a functional role of Prdm2 in alcohol-associated behaviors. In the work that constitutes this thesis, we have further investigated the behavioral consequences of Syt1 and Prdm2 downregulation. We found that Syt1 knock-down in the PL of non-dependent rats is sufficient to promote several behaviors that model critical aspects of AUD. We further identified the PL-basolateral amygdala (BLA) projection as a key brain circuit within which Syt1 knock-down promotes compulsive-like alcohol intake. In another study, we showed that Prdm2 knock-down in the PL increases the expression of fear memory, a central feature of anxiety disorders. Knock-down after memory formation (consolidation) did not increase the fear expression, indicating that Prdm2 regulates fear memory consolidation. We further showed that knock-down of Prdm2 in the PL-BLA projection was sufficient to promote the increased fear expression. Transcriptome analysis specifically in neurons projecting from the PL to the BLA showed a marked up-regulation of genes involved in synaptogenesis, suggesting that Prdm2 downregulation leads to excessive fear by strengthening fear memory consolidation in the PL-BLA circuit. 

In a third study, we used a model of social defeat- and witness stress to investigate mechanisms of co-occurring escalated alcohol intake and increased anxiety-like behavior ("comorbidity"). We recapitulated the broad range of individual stress responses observed in human populations. With gene expression analysis, we identified a marked upregulation of Avp in the amygdala of rats with "co-morbid" characteristics, and this upregulation correlated with the magnitude of the comorbidity. 

Together, our findings highlight the contribution of epigenetic mechanisms in regulating the behavioral consequences of alcohol-dependence, and identify specific downstream target genes whose expression is influenced by alcohol-induced epigenetic reprogramming to mediate long-term behavioral consequences. Our work also identifies amygdala Avp as a possible neurobiological substrate of individual susceptibility for stress-induced alcohol- and anxiety-related behaviors.

Comorbidity between alcohol use and anxiety disorders is associated with more severe symptoms and poorer treatment outcomes than either of the conditions alone. There is a well-known link between stress and the development of these disorders, with post-traumatic stress disorder as a prototypic example. Post-traumatic stress disorder can arise as a consequence of experiencing traumatic events firsthand and also after witnessing them. Here, we used a model of social defeat and witness stress in rats, to study shared mechanisms of stress-induced anxiety-like behavior and escalated alcohol self-administration. Similar to what is observed clinically, we found considerable individual differences in susceptibility and resilience to the stress. Both among defeated and witness rats, we found a subpopulation in which exposure was followed by emergence of increased anxiety-like behavior and escalation of alcohol self-administration. We then profiled gene expression in tissue from the amygdala, a key brain region in the regulation of stress, alcohol use, and anxiety disorders. When comparing "comorbid" and resilient socially defeated rats, we identified a strong upregulation of vasopressin and oxytocin, and this correlated positively with the magnitude of the alcohol self-administration and anxiety-like behavior. A similar trend was observed in comorbid witness rats. Together, our findings provide novel insights into molecular mechanisms underpinning the comorbidity of escalated alcohol self-administration and anxiety-like behavior.

Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2 knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2 KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2 KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2 KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.

Low self-esteem is a common problem among adolescents and is related to psychiatric problems such as depression and anxiety. However, effective and available interventions primarily targeting low self-esteem are scarce, in particular for youths. To address this gap, the aim of this pilot study was to evaluate a novel internet-based Cognitive Behavioral Therapy (ICBT) program for low self-esteem in adolescents using a randomized controlled design. Fifty-two participants (15-19 years) were recruited and randomly allocated to seven weeks of therapist-supported ICBT (n=26) or to a waitlist control condition (n=26). The primary outcome was the Rosenberg Self-Esteem Scale (RSES). Secondary outcomes measured domain-specific aspects of self-esteem, self-compassion, quality of life, depression and anxiety. The treatment group showed significantly higher levels of self-rated self-esteem compared to the control group at post-treatment, with a large between-group effect-size (RSES, d = 1.18). Further, the treatment had significant positive impact on secondary measures of self-esteem, self-compassion, quality of life, depression and anxiety. The results of this pilot-RCT suggest that ICBT can be effective for treating low self-esteem in adolescents, decrease depression and anxiety levels, and increasing quality of life. Replication of the results in larger samples is needed.    

Background Increased awareness of anxiety in adolescents emphasises the need for effective interventions. Internet-based cognitive behavioural therapy (ICBT) could be a resource-effective and evidence-based treatment option, but little is known about how to optimize ICBT or which factors boost outcomes. Recently, the role of knowledge in psychotherapy has received increased focus. Further, chat-sessions are of interest when trying to optimize ICBT for youths. This study aimed to evaluate the role of learning support and chat-sessions during ICBT for adolescent anxiety, using a factorial design. Method A total of 120 adolescents were randomised to one of four treatment groups, in a 2x2 design with two factors: with or without learning support and/or chat-sessions. Results Anxiety and depressive symptoms were reduced (Beck Anxiety Inventory- BAI; Cohensd=0.72; Beck Depression Inventory- BDI;d=0.97). There was a main effect of learning support on BAI (d=0.38), and learning support increased knowledge gain (d =0.42). There were no main effects or interactions related to the chat-sessions. Treatment effects were maintained at 6-months, but the added effect of learning support had by then vanished. Conclusion ICBT can be an effective alternative when treating adolescents with anxiety. Learning support could be of importance to enhance short-term treatment effects, and should be investigated further.

Major depressive disorder (MDD) is one of the most significant contributors to the global burden of illness. Diffusion tensor imaging (DTI) is a procedure that has been used in several studies to characterize abnormalities in white matter (WM) microstructural integrity in MDD. These studies, however, have provided divergent findings, potentially due to the large variety of methodological alternatives available in conducting DTI research. In order to determine the importance of different approaches to coregistration of DTI-derived metrics to a standard space, we compared results from two different skeletonized voxel-wise analysis approaches: the standard TBBS pipeline and the Advanced Normalization Tools (ANTs) approach incorporating a symmetric image normalization (SyN) algorithm and a group-wise template (ANTs TBSS). We also assessed effects of applying twelve different fitting procedures for the diffusion tensor. For our dataset, lower fractional anisotropy (FA) and axial diffusivity (AD) in depressed subjects compared with healthy controls were found for both methods and for all fitting procedures. No group differences were found for radial and mean diffusivity indices. Importantly, for the AD metric, the normalization methods and fitting procedures showed reliable differences, both in the volume and in the number of significant between-groups difference clusters detected. Additionally, a significant voxel-based correlation, in the left inferior fronto-occipital fasciculus, between AD and self-reported stress was found only for one of the normalization procedure (ANTs TBSS). In conclusion, the sensitivity to detect group-level effects on DTI metrics might depend on the DTI normalization and/or tensor fitting procedures used.

Aim: To improve consistency between register studies in Sweden and ensure valid comparisons of possible changes in alcohol-related disorders and diseases (ARDDs) over time, we propose a definition of ARDDs. Based on this definition, we examined Sweden's incidence rates of ARDDs from 1970 to 2018 in non-primary healthcare settings (inpatient and outpatient).

Methods: Swedish Society of Epidemiology members were invited to give feedback on the International Classification of Disease (ICD) codes with a potential link to alcohol use. We then calculated age-standardised and age-specific incidence of ARDDs over time according to the National Patient Register, and the lifetime prevalence of ARDDs diagnosed in adults alive in Sweden on Dec 31, 2018.

Results: Sweden's estimated incidence of ARDDs increased substantially after introducing the new ICD-9 codes in 1987. In the past 10 years (2009-2018), the incidence of ARDDs has been stable (males: 110/100,000 person-years, females: 49/100,000 person-years). Requiring at least two ICD records for diagnosed ARDDs led to a somewhat lower incidence of ARDDs (males: 71 per 100,000 person-years, females: 29 per 100,000 person-years). In Sweden, the lifetime prevalence of diagnosed ARDDs in adults on Dec 31, 2018, was 1.9% (95% CI=1.9-1.9).

Conclusion: In this nationwide study, we found an incidence of ARDDs of 50-100/100,000 person-years. In 2018, 1 in 52 adults in Sweden had been diagnosed with ARDDs in the National Patient Register.

Acetaminophen (paracetamol) is often used in critically ill patients with fever and pain; however, little is known about the effects of acetaminophen on cardiovascular function during systemic inflammation. Here, we investigated the effect of acetaminophen on changes in the systemic and pulmonary circulation induced by endotoxin (0.5 mu g/kg per hour) in anesthetized pigs. Endotoxin infusion led to a rapid increase in pulmonary artery pressure and pulmonary vascular resistance index. Acetaminophen delayed and attenuated this increase. Furthermore, acetaminophen reduced tachycardia and decreased stroke volume, accompanied by systemic inflammation, without affecting inflammatory parameters such as white blood cell count and TNF-alpha in blood. As a proof of concept, we injected a high dose of endotoxin (100 mu g), which induced rapid cardiovascular collapse in pigs. Pigs treated with acetaminophen survived with no obvious hemodynamic instability during the 50-min observation period. In conclusion, acetaminophen attenuates the effects of endotoxin on pulmonary circulation in anesthetized pigs. This may play a role in severe systemic inflammation.

Enteric glial cells (EGC) are known to regulate gastrointestinal functions; however, their role in Crohns disease (CD) is elusive. Microscopic erosions over the ileal Peyers patches are early signs of CD. The aim of this work was to assess the localization of EGC in the follicle and interfollicular region of the Peyers patches and in the lamina propria and study the effects of EGC mediators on barrier function in CD patients and non-inflammatory bowel disease (non-IBD) controls. EGC markers, glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein β (S100β) were quantified by immunofluorescence and Western blotting. Both markers showed significantly more EGC in the Peyers patches and lamina propria of CD patients compared to the non-IBD controls. In CD patients there were significantly more EGC in Peyers patches compared to lamina propria, while the opposite pattern was seen in controls. Barrier function studies using Ussing chambers showed increased paracellular permeability by EGC mediators in CD patients, whereas permeability decreased by the mediators in controls. We show the accumulation of EGC in Peyers patches of CD patients. Moreover, EGC mediators induced barrier dysfunction in CD patients. Thus, EGC might have harmful impacts on ongoing inflammation and contribute to the pathophysiology of the disease.

Objective: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. Methods: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). Results: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. Conclusion: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex-specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Background Numerous resting-state studies on attention deficit hyperactivity disorder (ADHD) have reported aberrant functional connectivity (FC) between the default-mode network (DMN) and the ventral attention/salience network (VA/SN). This finding has commonly been interpreted as an index of poorer DMN regulation associated with symptoms of mind wandering in ADHD literature. However, a competing perspective suggests that dysfunctional organization of the DMN and VA/SN may additionally index increased sensitivity to the external environment. The goal of the current study was to test this latter perspective in relation to auditory distraction by investigating whether ADHD-adults exhibit aberrant FC between DMN, VA/SN, and auditory networks. Methods Twelve minutes of resting-state fMRI data was collected from two adult groups: ADHD (n = 17) and controls (n = 17); from which the FC between predefined regions comprising the DMN, VA/SN, and auditory networks were analyzed. Results A weaker anticorrelation between the VA/SN and DMN was observed in ADHD. DMN and VA/SN hubs also exhibited aberrant FC with the auditory network in ADHD. Additionally, participants who displayed a stronger anticorrelation between the VA/SN and auditory network at rest, also performed better on a cognitively demanding behavioral task that involved ignoring a distracting auditory stimulus. Conclusion Results are consistent with the hypothesis that auditory distraction in ADHD is linked to aberrant interactions between DMN, VA/SN, and auditory systems. Our findings support models that implicate dysfunctional organization of the DMN and VA/SN in the disorder and encourage more research into sensory interactions with these major networks.

Objectives: Infections, cancer, and systemic inflammation elicit anorexia. Despite the medical significance of this phenomenon, the question of how peripheral inflammatory mediators affect the central regulation of food intake is incompletely understood. Therefore, we have investigated the sickness behavior induced by the prototypical inflammatory mediator IL-1 beta. Methods: IL-1 beta was injected intravenously. To interfere with IL-1 beta signaling, we deleted the essential modulator of NF-kappa B signaling (Nemo) in astrocytes and tanycytes. Results: Systemic IL-1 beta increased the activity of the transcription factor NF-kB in tanycytes of the mediobasal hypothalamus (MBH). By activating NF-kappa B signaling, IL-1 beta induced the expression of cyclooxygenase-2 (Cox-2) and stimulated the release of the anorexigenic prostaglandin E-2 (PGE(2)) from tanycytes. When we deleted Nemo in astrocytes and tanycytes, the IL-1 beta-induced anorexia was alleviated whereas the fever response and lethargy response were unchanged. Similar results were obtained after the selective deletion of Nemo exclusively in tanycytes. Conclusions: Tanycytes form the brain barrier that mediates the anorexic effect of systemic inflammation in the hypothalamus. (C) 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Attention deficit hyperactivity disorder (ADHD) and Autism Spectrum Disorder (ASD) are often accompanied by sleep problems influencing social, emotional and cognitive functioning in everyday activities. Aim The aim of this study was to investigate whether the use of a weighted blanket has a positive impact on sleep and everyday activities in individuals with ADHD and/or ASD. Material and methods The study included 85 individuals diagnosed with ADHD and/or ASD, 48 children aged <= 17 (57%) and 37 adults >= 18 years (44%), who were prescribed with a weighted blanket. The participants responded via a telephone interview. Results Findings demonstrated that a weighted blanket improved abilities related to falling asleep, sleeping the whole night, and relaxing during the day. Using a weighted blanket improved morning/evening daily routine, including preparing/going to sleep and waking up in the morning. Conclusions Weighted blankets showed positive impact on falling asleep, sleeping the whole night, and relaxing during the day, and they were used frequently by children and adults with ADHD and/or ASD. Findings indicate that a weighted blanket improved morning/evening routine, however this research area needs further investigation using both subjective and objective parameters.

Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed. The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.

Lipopolysaccharide (LPS) induces fever through cytokines like receptor-activator of nuclear factor kappa B ligand (RANKL), triggering mediators like prostaglandins (PG), endothelin-1 (ET-1), corticotrophin-releasing factor (CRF), substance P (SP) and endogenous opioids. LPS-induced fever is reduced in females compared with males except in ovariectomized (OVX) females which show increased fever mediated by PG. The present study aimed to identify the mediators involved in fever in intact and OVX female rats. Fever was induced with LPS (50 mu g/kg) intraperitoneally or CRF (2.5 mu g), ET-1 (1 pg), morphine (10 mu g) and SP (500 ng) intracerebroventricularly in sham-operated and OVX rats. The role of RANKL was evaluated with osteoprotegerin (OPG, 1 mu g, intracerebroventricularly). Expression of RANK, CRFI/II, ETB, mu-opioid (MOR) and NK1 receptors was evaluated by confocal microscopy. Besides LPS, only morphine induced fever in OVX rats while all mediators induced fever in sham-operated animals. OPG abolished LPS-induced fever in OVX but not sham-operated animals. Overall, fever involves similar central mediators in cycling females and males but only morphine induced fever in OVX females. Importantly, RANK/RANKL participates in LPS-induced fever in OVX females, as in males but not in cycling females.

Context/Objective:Spinal cord injury (SCI) causes atrophy of brain regions linked to motor function. We aimed to estimate cortical thickness in brain regions that control surgically restored limb movement in individuals with tetraplegia. Design:Cross-sectional study. Setting:Sahlgrenska University hospital, Gothenburg, Sweden. Participants:Six individuals with tetraplegia who had undergone surgical restoration of grip function by surgical transfer of one elbow flexor (brachioradialis), to the paralyzed thumb flexor (flexor pollicis longus). All subjects were males, with a SCI at the C6 or C7 level, and a mean age of 40 years (range = 31-48). The average number of years elapsed since the SCI was 13 (range = 6-26). Outcome measures:We used structural magnetic resonance imaging (MRI) to estimate the thickness of selected motor cortices and compared these measurements to those of six matched control subjects. The pinch grip control area was defined in a previous functional MRI study. Results:Compared to controls, the cortical thickness in the functionally defined pinch grip control area was not significantly reduced (P = 0.591), and thickness showed a non-significant but positive correlation with years since surgery in the individuals with tetraplegia. In contrast, the anatomically defined primary motor cortex as a whole exhibited substantial atrophy (P = 0.013), with a weak negative correlation with years since surgery. Conclusion:Individuals with tetraplegia do not seem to have reduced cortical thickness in brain regions involved in control of surgically restored limb movement. However, the studied sample is very small and further studies with larger samples are required to establish these findings.

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Objectives: Opioid analgesics are essential in clinical practice, but their excessive use is associated with addiction risk. Increases in opioid prescription rates have fuelled an epidemic of opioid addiction in the USA, making statistics on medical opioid use a critical warning signal. A dramatic 150% increase in Swedish opioid access 2001-2013 was recently reported based on data from the International Narcotics Control Board (INCB; Berterame et al. 2016) in conflict with other studies of opioid use in the Nordic countries. This article aims to analyse to what degree published INCB statistics on opioids in Scandinavia (Denmark, Norway and Sweden) reflect actual medical use and study the methodological reasons for putative discrepancies. Methods: Data on aggregated total national sales of opioids for the whole population, including hospitals, were collected from the Swedish e-Health Authority. Total sales data for Denmark and drugs dispensed at pharmacies in Norway are publicly available through the relevant authorities websites. Results: INCB opioid statistics during the period 2001-2013 were markedly inconsistent with sales data from Scandinavia, calling the reliability of INCB data into question. INCB-data were flawed by (a) over-representing the volume of fentanyl, (b) under-reporting of codeine, and (c) by not including tramadol. Conclusions: Opioid availability, as expressed by INCB statistics, does not reflect medical opioid use. It is crucial to underline that INCB statistics are based on the manual compilation of national production, import and export data from manufacturers and drug companies. This is not the same amount that is prescribed and consumed within the health care system. Moreover, there are methodological problems in the INCB reports, in particular concerning fentanyl, codeine and tramadol. We suggest that INCB should carefully review the quality of their data on medical opioids.

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 unknown. Differentiation of self- and non-self- generated sensations might be key to understand and develop novel strategies for managing hypersensitivity. Here, we compared the neural signatures of affective self- and other-touch between adults with ADHD and neurotypical controls (NC).

Methods

Twenty-eight adult ADHD participants and 30 age- and gender-matched NC performed a self-other-touch-task during functional magnetic resonance imaging: they stroked their own arm, an object, or were stroked by the experimenter. In addition, tactile detection thresholds and rubber hand illusion (RHI) were measured.

Results

ADHD participants had more autistic traits than NC and reported to engage less in interpersonal touch. They also reported to be more sensitive to tactile stimuli. Compared to NC, ADHD participants showed enhanced responses to both the self- and other-touch conditions: stronger deactivation during self-touch in the anterior and posterior insula, and increased activation during other-touch in primary somatosensory cortex. ADHD participants had intact tactile detection thresholds, but were less susceptible to the RHI.

Conclusions

Unaltered detection thresholds suggest that peripheral processing is intact, and that hypersensitivity might be driven by central mechanisms. This has clinical implications for managing somatosensory hypersensitivity in ADHD. The more pronounced differentiation between self- and other-touch might indicate a clearer self-other-distinction. This is of interest regarding body ownership perception in both NC and ADHD, and possibly other psychiatric conditions with altered self-experiences, like schizophrenia. A sharper boundary of the own body might relate to deficits in social cognition and tactile hypersensitivity.

Humans need to be able to differentiate between signals they produce themselves and signals that arise from non-self-causes. It has long been discussed that the brain uses a copy of the motor command, an efference copy, to predict the sensory outcomes of ones own action - and to attenuate these. While studies in humans suggest that cerebellum and supplementary motor area play crucial roles in the attenuation, a study in mice suggests a global suppression during self-touch. However, the sensory percepts of self-touch are not fully cancelled out. Humans touch themselves frequently suggesting a behavioral relevance of self-touch, as to refocus attention, to calm oneself down during stress, to itch or for self-enjoyment. We discuss studies on sensory attenuation as well as the behavioral relevance of self-touch and open questions for future research.

Social touch is important for interpersonal interaction. Gentle touch and slow brushing are typically perceived as pleasant, the degree of pleasantness is linked to the activity of the C-tactile (CT) fibers, a class of unmyelinated nerves in the skin. The inability to experience pleasure in general is called anhedonia, a common phenomenon in the chronic pain condition fibromyalgia. Here, we studied the perception and cortical processing of gentle touch in a well-characterized cohort of fibromyalgia. Patients and controls participated in functional brain imaging while receiving tactile stimuli (brushing) on the forearm. They were asked to provide ratings of pleasantness of the tactile stimulus and ongoing pain. We found high distress, pain catastrophizing, and insomnia, and a low perceived state of health in fibromyalgia. Further, patients rated both slow (CT-optimal) and fast (CT-suboptimal) brushing as less pleasant than healthy participants. While there was no difference in brain activity during touch, patients showed deactivation in the right posterior insula (contralateral to the stimulated arm) during pleasantness rating and activation during pain rating. The opposite pattern was observed in healthy participants. Voxel-based morphometry analysis revealed reduced grey matter density in patients, in the bilateral hippocampus and anterior insula. Our results suggest anhedonia to gentle touch in fibromyalgia with intact early-stage sensory processing but dysfunctional evaluative processing. These findings contribute to our understanding of the mechanisms underlying anhedonia in fibromyalgia.

Eosinophils have been linked to functional dyspepsia; however, less is known about their role in irritable bowel syndrome (IBS). This study tested the hypothesis of alterations in levels of fecal eosinophil-derived neurotoxin (F-EDN) and eosinophil density and degranulation within the colonic mucosa of IBS patients compared with healthy controls (HC). Colonic biopsies were collected from 37 IBS patients and 20 HC and analyzed for eosinophil numbers and local degranulation of eosinophil cationic protein (ECP) by histologic procedures. Fecal samples were collected for F-EDN and microbiota analysis. Differentiated 15HL-60 cells were used in vitro to investigate the direct effect of live bacteria on eosinophil activation measured by a colorimetric assay with o-phenylenediamine (OPD) substrate. We observed a higher number of eosinophils and increased extracellular ECP in the mucosa of IBS patients compared with HC. Moreover, F-EDN levels in IBS samples were elevated compared with HC and positively correlated to extracellular ECP. Metagenomic analysis showed significant correlations between bacterial composition and eosinophil measurements in both HC and IBS patients. In vitro experiments revealed an increased degranulation of 15HL-60 after stimulation with Salmonella typhimurium, Salmonella enterica, and Yersinia enterocolitica. To conclude, we could demonstrate alterations related to eosinophils in IBS, and, for the first time, a positive correlation between F-EDN levels and degranulated eosinophils in the colonic mucosa of IBS patients. Together our results suggest that eosinophils play a role in the pathophysiology of IBS and the mechanisms might be linked to an altered microbiota.

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking A beta fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for A beta afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection. The mechanisms underlying deep pressure sensing are not fully understood. Here the authors demonstrate that while two individuals lacking A beta fibers demonstrate impaired deep pressure sensing, seven individuals with PIEZO2 loss of function mutations display normal deep pressure responses.

Neuroscientific research on pleasant touch has focused on the C-tactile pathway for gentle stroking and has successfully explained how these sensory fibers transmit information about affective social touch to the brain and induce sensations of pleasantness. The C-tactile social/affective touch hypothesis even proposes that C-tactile fibers form a privileged pathway underlying social touch. However, deep pressure is a type of touch commonly considered pleasant and calming, occurring in hugs, cuddling, and massage. In this paper we introduce a paradigm for studying pleasant deep pressure and propose that it constitutes another important form of social touch. We describe development of the oscillating compression sleeve (OCS) as one approach to administering deep pressure and demonstrate that this touch is perceived as pleasant and calming. Further, we show that deep pressure can be imaged with functional magnetic resonance imaging (MRI) using the air-pressure driven OCS and that deep pressure activates brain regions highly similar to those that respond to C-tactile stroking, as well as regions not activated by stroking. We propose that deep pressure constitutes another social touch pathway of evolutionary importance signaling the close proximity of conspecifics. This article is part of a Special Issue entitled: The Neurobiology of Social and Affective Touch. (c) 2020 The Authors. Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). research on pleasant touch has focused on the C-tactile pathway for gentle stroking and has successfully explained how these sensory fibers transmit information about affective social touch to the brain and induce sensations of pleasantness. The C-tactile social/affective touch hypothesis even proposes that C-tactile fibers form a privileged pathway underlying social touch. However, deep pressure is a type of touch commonly considered pleasant and calming, occurring in hugs, cuddling, and massage. In this paper we introduce a paradigm for studying pleasant deep pressure and propose that it constitutes another important form of social touch. We describe development of the oscillating compression sleeve (OCS) as one approach to administering deep pressure and demonstrate that this touch is perceived as pleasant and calming. Further, we show that deep pressure can be imaged with functional magnetic resonance imaging (MRI) using the air-pressuredriven OCS and that deep pressure activates brain regions highly similar to those that respond to C-tactile stroking, as well as regions not activated by stroking. We propose that deep pressure constitutes another social touch pathway of evolutionary importance signaling the close proximity of conspecifics. This article is part of a Special Issue entitled: The Neurobiology of Social and Affective Touch. (c) 2020 The Authors. Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Loneliness is a significant problem for young people and is associated with a range of physical and mental health difficulties. Meta-analyses have identified that interventions aimed at young people who report loneliness as their primary problem are lacking within the literature. In adults, the most effective interventions for loneliness are those which target the underlying maladaptive social cognitions. Therefore, we have developed a modular Cognitive Behavioural Therapy (CBT) intervention for children and young people. The aim of this study is to conduct a multiple baseline single-case experimental design (SCED) to assess the efficacy, feasibility and acceptability of this intervention. In total 6-8 11-18-year-olds and their families will be recruited. The design consists of AB+ post-intervention, where A is the baseline phase, B is the intervention phase and then a post-intervention phase. Participants will complete a baseline assessment, before being randomised to one of four different baseline lengths (12 days, 19 days, 26 days or 33 days). Participants will then complete an average of 12 sessions of CBT, with the aim being to reduce their feelings of loneliness. Participants will then complete a 12-day post-intervention phase. Participant loneliness will be repeatedly assessed throughout the three phases of the intervention using the Three-item Loneliness Scale, which will be the primary outcome. Secondary outcomes will be reliable and clinically meaningful change on the UCLA Loneliness Scale, Revised Child Anxiety and Depression Scale (RCADS) and Strengths and Difficulties Questionnaire (SDQ). Feasibility and participant satisfaction will also be assessed and reported.

Aggression is a complex social behavior that evolved in the context of defending a territory, fighting for limited resources, and competing for mates and protection. Although aggression considered as a negative or undesirable emotion is an essential part of many species repertoire of social behaviors. For humans, the motivations, actions, and limits of aggressive acts are not always clear. However, uncontrolled aggression may have destructive consequences, and it develops inappropriately into violence. At the neural level, several studies demonstrated that aggression is related to cortical abnormalities, including the anterior cingulate cortex (ACC). This review summarizes the state of the literature regarding the involvement of ACC in the neurobiology of aggression and impulsivity. We will first review structural and neuroanatomical studies, including volumetric and functional investigations of aggression. Next, we will discuss the neurochemical and neuropharmacological studies of aggression related to the ACC. We will focus mainly on the gamma-aminobutyric acid/glutamate balance, as well as the serotoninergic system. Finally, we will try to integrate these results and reconcile discrepancies in the field and suggest recommendations for future studies.

BACKGROUND Mortality among patients admitted to intensive care units (ICUs) with COVID-19 is unclear due to variable follow-up periods. Few nationwide data are available to compare risk factors, treatment and outcomes of COVID-19 patients after ICU admission. OBJECTIVE To evaluate baseline characteristics, treatments and 30-day outcomes of patients admitted to Swedish ICUs with COVID-19. DESIGN Registry-based cohort study with prospective data collection. SETTING Admissions to Swedish ICUs from 6 March to 6 May 2020 with laboratory confirmed COVID-19 disease. PARTICIPANTS Adult patients admitted to Swedish ICUs. EXPOSURES Baseline characteristics, intensive care treatments and organ failures. MAIN OUTCOMES AND MEASURES The primary outcome was 30-day all-cause mortality. A multivariable model was used to determine the independent association between potential predictor variables and death. RESULTS We identified 1563 patients with complete 30-day follow-up. The 30-day all-cause mortality was 26.7%. Median age was 61 [52 to 69], Simplified Acute Physiology Score III (SAPS III) was 53 [46 to 59] and 62.5% had at least one comorbidity. Median PaO2/FiO(2) on admission was 97.5 [75.0 to 140.6] mmHg, 74.7% suffered from moderate-to-severe acute respiratory failure. Age, male sex [adjusted odds ratio (aOR) 1.5 (1.1 to 2.2)], SAPS III score [aOR 1.3 (1.2 to 1.4)], severe respiratory failure [aOR 3.0 (2.0 to 4.7)], specific COVID-19 pharmacotherapy [aOR 1.4 (1.0 to 1.9)] and continuous renal replacement therapy [aOR 2.1 (1.5 to 3.0)] were associated with increased mortality. Except for chronic lung disease, the presence of comorbidities was not independently associated with mortality. CONCLUSIONS Thirty-day mortality rate in COVID-19 patients admitted to Swedish ICUs is generally lower than previously reported despite a severe degree of hypoxaemia on admission. Mortality was driven by age, baseline disease severity, the presence and degree of organ failure, rather than pre-existing comorbidities.

Familjepsykoterapi är en behandlingsmetod som möjliggör en förändring av de relationer som skapar och vidmakthåller vissa psykiska eller fysiska symtom hos barn, unga och vuxna. Till grund för familjepsykoterapi ligger antagandet att symtom på psykisk och fysisk ohälsa kan uppstå och vidmakthållas av och i olika system av relationer.

De teoretiska grundvalarna för familjepsykoterapi är primärt systemteori, cybernetik och kommunikationsteori. Men för att teorier inte ska förbli teoretiska resonemang behöver de med hjälp av en systemteoretisk analys länkas samman med den kliniska nivån i syfte att synliggöra och förstå interaktionen i det unika familjesystemet och mot bakgrund av det utforma en hypotes för behandling.

Boken beskriver de teorier som utgör grundvalen för familjepsykoterapi och ger konkreta exempel på hur teorierna länkas samman med olika familjer och par i den systemteoretiska analysen. Den avslutas med en begreppstabell med primär- och sekundärkällor angivna. 

Boken vänder sig till familjepsykoterapistudenter samt studenter vid utbildning till bland annat psykoterapeut, läkare, sjuksköterska, socionom och psykolog. Den kan också utgöra en repetition och grundbok för etablerade familjepsykoterapeuter och handledare. Även en intresserad allmänhet som undrar vad familjepsykoterapi innebär kan ha glädje av boken.

Social anxiety disorder (SAD) can come in different forms, presenting problems for diagnostic classification. Here, we examined personality traits in a large sample of patients (N = 265) diagnosed with SAD in comparison to healthy controls (N = 164) by use of the Revised NEO Personality Inventory (NEO-PI-R) and Karolinska Scales of Personality (KSP). In addition, we identified subtypes of SAD based on cluster analysis of the NEO-PI-R Big Five personality dimensions. Significant group differences in personality traits between patients and controls were noted on all Big Five dimensions except agreeableness. Group differences were further noted on most lower-order facets of NEO-PI-R, and nearly all KSP variables. A logistic regression analysis showed, however, that only neuroticism and extraversion remained significant independent predictors of patient/control group when controlling for the effects of the other Big Five dimensions. Also, only neuroticism and extraversion yielded large effect sizes when SAD patients were compared to Swedish normative data for the NEO-PI-R. A two-step cluster analysis resulted in three separate clusters labelled Prototypical (33%), Introvert-Conscientious (29%), and Instable-Open (38%) SAD. Individuals in the Prototypical cluster deviated most on the Big Five dimensions and they were at the most severe end in profile analyses of social anxiety, self-rated fear during public speaking, trait anxiety, and anxiety-related KSP variables. While additional studies are needed to determine if personality subtypes in SAD differ in etiological and treatment-related factors, the present results demonstrate considerable personality heterogeneity in socially anxious individuals, further underscoring that SAD is a multidimensional disorder.