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1.	Bas-Hoogendam, Janna Marie, et al. (författare) Sample Size Matters : A Voxel-Based Morphometry Multi-Center Mega-Analysis of Gray Matter Volume in Social Anxiety Disorder 2017 Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 81:10, s. S7-S7 Tidskriftsartikel (refereegranskat)
2.	Bas-Hoogendam, Janna Marie, et al. (författare) Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder 2017 Ingår i: NeuroImage. - : Elsevier BV. - 2213-1582. ; 16, s. 678-688 Tidskriftsartikel (refereegranskat)abstract Social anxiety disorder (SAD) is a prevalent and disabling mental disorder, associated with significant psychiatric co-morbidity. Previous research on structural brain alterations associated with SAD has yielded inconsistent results concerning the direction of the changes in gray matter (GM) in various brain regions, as well as on the relationship between brain structure and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multi-site imaging offers new opportunities to investigate SAD-related alterations in brain structure in larger samples.An international multi-center mega-analysis on the largest database of SAD structural T1-weighted 3T MRI scans to date was performed to compare GM volume of SAD-patients (n = 174) and healthy control (HC)-participants (n = 213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, the amygdala-hippocampal complex, the prefrontal cortex, and the parietal cortex. SAD-patients had larger GM volume in the dorsal striatum when compared to HC-participants. This increase correlated positively with the severity of self-reported social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs. Thereby, the results of this mega-analysis suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Our findings emphasize the importance of large sample imaging studies and the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium.
3.	Brännström, Jonas, et al. (författare) The initial evaluation of an Internet-based support system for audiologists and first-time hearing aid clients 2016 Ingår i: Internet Interventions. - : Elsevier BV. - 2214-7829. ; 4, s. 82-91 Tidskriftsartikel (refereegranskat)abstract Objectives: Audiologists provide professional contact and support between appointments to clients with hearing impairment using telephone and e-mail, but more advanced and flexible technological platforms are also possible. The present study aimed to evaluate the clinical application of an Internet-based support system for audiologists and their first-time hearing aid clients. Design: An Internet-based support system developed by Månsson et al. (2013) for psychologists and their clients was adapted for audiologic purposes. Three audiologic clinics in Sweden tested the support system with their clients. Study sample: Twenty-three clients managed by four audiologists used and evaluated the support system. In addition, five of the clients and all four audiologists were interviewed and their responses were analyzed using content analysis. Results: The clients and the audiologists reported positive experiences and overall satisfaction but audiologists reported that the support system did not address the needs of all clients. More positive experiences and greater satisfaction with the support system were associated with reductions on self-reported consequences of hearing loss and positive hearing aids outcomes. Conclusions: An Internet-based support system can be used in audiologic rehabilitation. Both audiologists and clients recognized the system's potential value to offer an online support to the provision of audiologic services.
4.	Brännström, Jonas, et al. (författare) The initial evaluation of an internet-based support system for audiologists and first-time hearing aid clientsThe process of developing an internet-based support system for audiologists and first-time hearing aid clients 2016 Ingår i: Internet Interventions. - : Elsevier. - 2214-7829. ; 4:1, s. 82-91 Tidskriftsartikel (refereegranskat)
5.	Brännström, Jonas, et al. (författare) The Process of Developing an Internet-Based Support System for Audiologists and First-Time Hearing Aid Clients 2015 Ingår i: American Journal of Audiology. - : American Speech-Language-Hearing Association. - 1059-0889 .- 1558-9137. ; 24:3, s. 320-324 Tidskriftsartikel (refereegranskat)abstract Background: In audiologic practice, complementary information sources and access to the clinician between appointments improve information retention and facilitate adjustment behaviors. An Internet-based support system is a novel way to support information sharing and clinician access. Purpose: This research forum article describes the process of developing an Internet-based support system for audiologists and their first-time hearing aid clients. Method: The iterative development process, including revisions by 4 research audiologists and 4 clinical audiologists, is described. The final system is exemplified. Conclusion: An Internet-based support system was successfully developed for audiologic practice.
6.	Cortes, Diana S., et al. (författare) Increased dorsomedial prefrontal cortex activity to negative emotion displays in men but not in women 2019 Ingår i: Program. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract The neuropeptide oxytocin plays a prominentrole in social and emotional cognition. Findings suggest that exogenous intranasal oxytocin administration facilitates emotion recognition in humans, but individual and contextual differences may have moderating effects. A major caveat in this line of work is that it is predominantly based on young males, which limits current knowledge and potential for generalizability across gender. To uncover potential gender effects, the present study included younger and older men and women. Utilizing a randomized, double-blind, placebo-controlled, within-subjects study design, we investigated the effects of a single-dose of 40 IUs intranasal oxytocin administration on emotion recognition of dynamic positive and negative stimuli in 32 men (mean age 45.78, sd. 22.87) and 39 women (mean 47.87, sd. 47.87), 40 minutes prior to MRI scanning. Preliminary analyses show that oxytocin induced brain activity reductions during exposure to negative (relative to positive) stimuli in women, while increasing brain activity in dorsomedial prefrontal cortex in men. We speculate that the effects of oxytocin on emotion recognition may possibly be related to emotion regulation and mentalization processes, and that oxytocin is related to potential sex-differences in these processes. The results also raise concern that previous oxytocin literature on emotion recognition may be biased as there appears to be gender-differential effects of oxytocin on brain activity across adulthood that have been underestimated. In the next stage of the present study, we will investigate the interaction effects among treatment, sex, age, and presentation modality.
7.	Cortes, Diana S., et al. (författare) Oxytocin Induces Brain Activity Reductions to Negative Emotional Stimuli in Younger and Older Adults 2018 Konferensbidrag (refereegranskat)abstract In recent years, the intranasal administration of the neuropeptide oxytocin has mainly been related to improvements in domains such as emotion recognition and memory, but to date the effects of oxytocin in aging remain largely unknown. A major caveat in oxytocin research is that it is almost exclusively based on young men which may reflect an inadequate picture of the potential benefits of oxytocin administration. In a randomized, double blind, placebo controlled, within-subjects study design, we investigated whether oxytocin affects the recognition of positive and negative stimuli differently in younger and older adults. Forty-four older adults (50% women; M= 69.82) and 44 younger adults (50% women; M= 24.75) participated in this study two times, receiving a single intranasal dose of 40 IUs of placebo and oxytocin in randomized order 40 minutes before engaging in the task. Participants watched short videoclips where actors displayed nine emotions: neutrality, happiness, pride, interest, relief, anger, despair, sadness, and disgust. Preliminary results indicate that oxytocin-induced reductions to negative emotions were found in bilateral fusiform gyrus (Z > 4.16, Family wise error corrected, pFWE < 0.009), hippocampus (Z > 4.53, pFWE < 0.002), insula (Z > 3.69, pFWE < 0.045), and superior temporal gyrus (Z > 4.34, pFWE < 0.008), as well as, right-lateralized reductions in the amygdala (Z = 3.73, pFWE = 0.005). These findings are in line with previous studies showing decreased brain activity to negative stimuli and suggest that this mechanism in not only present in younger adults but it can also be extended to an older population. Future studies should investigate how oxytocin impacts socioemotional and cognitive processes in elderly.
8.	Cortes, Diana S., et al. (författare) Oxytocin may facilitate neural recruitment in medial prefrontal cortex and superior temporal gyrus during emotion recognition in young but not older adults 2020 Ingår i: 2020 Cognitive Aging Conference. ; , s. 22-23 Konferensbidrag (refereegranskat)abstract Normal adult aging is associated with decline in some socioemotional abilities, such as the ability to recognize emotions in others, and age-related neurobiological processes may contribute to these deficits. There is increasing evidence that the neuropeptide oxytocin plays a key role in social cognition, including emotion recognition. The mechanisms through which oxytocin promotes emotion recognition are not well understood yet, and particularly in aging. In a randomized, double-blind, placebo-controlled within-subjects design, we investigated the extent to which a single dose of 40 IU of intranasal oxytocin facilitates emotion recognition in 40 younger (M = 24.90 yrs., SD = 2.97, 48% women) and 40 older (M = 69.70 yrs., SD = 2.99, 55% women) men and women. During two fMRI sessions, participants viewed dynamic positive and negative emotional displays. Preliminary analyses show that younger participants recognized positive and negative emotions more accurately than older participants (p < .001), with this behavioral effect not modulated by oxytocin. In the brain data, however, we found an age x treatment interaction in medial prefrontal cortex (xyz [14, 14, 6], p = .007) and superior temporal gyrus (xyz [53, 9, 2], p = .031). In particular, oxytocin (vs. placebo) reduced activity in these regions for older participants, while it enhanced activity in these regions for younger participants. In line with previous research, these findings support the notion that the effects of oxytocin vary by context and individual factors (e.g., social proficiency, age).
9.	Cortes S., Diana, et al. (författare) Does single-dose intranasal oxytocin facilitate neural recruitment in younger and older adults during negative compared to positive dynamic multimodal expressions? Tidskriftsartikel (refereegranskat)abstract Normal adult aging is associated with a decline in socioemotional abilities, and underlying these deficits are age-related neurobiological processes. There is increasing evidence that the neuropeptide oxytocin plays a key role in social cognition, specifically in the ability to recognize emotions. In a randomized, double-blind, placebo controlled within-subjects design, we investigated the extent to which a single dose of 40 IU of intranasal oxytocin facilitates neural recruitment in younger and older adults during negative compared to positive dynamic multimodal expressions. Based on the literature, several regions of interest were selected prior analyses: insula, amygdala, caudate head, fusiform gyrus, superior temporal gyrus, medial prefrontal cortex, medial orbitofrontal cortex, ventral medial prefrontal cortex, and dorsomedial prefrontal cortex. Behavioral data showed that younger adults outperformed older adults. and higher accuracy scores were observed during the PL condition compared to the OT condition. This was further qualified by the brain data, where OT induced brain activity reductions in the fusiform gyrus, dorsomedial prefrontal cortex, and medial orbitofrontal cortex in response to negative compared to positive expressions. Both age groups showed hypoactivity in most regions of interest during auditory stimuli compared to visual and multimodal stimuli. In line with previous research, these findings suggest that the effects of oxytocin may vary due to context, social proficiency, and individual factors (i.e. age). Future studies should target how age, presentation modality, and oxytocin interact.
10.	Costache, Madalina Elena, et al. (författare) Higher- and lower-order personality traits and cluster subtypes in social anxiety disorder 2020 Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 15:4 Tidskriftsartikel (refereegranskat)abstract 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.
11.	Dawaigher, Sami, et al. (författare) A Protocol for the exo-Mono and exo,exo-Bis Functionalization of the Diazocine Ring of Tröger's Base. 2015 Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 1520-6904 .- 0022-3263. ; 80:24, s. 12006-12014 Tidskriftsartikel (refereegranskat)abstract An efficient protocol has been developed for the exo-mono and exo,exo-bis functionalization of Tröger's base in the benzylic 6 and 12 positions of the diazocine ring. The lithiation of Tröger's base using s-BuLi/TMEDA followed by electrophilic quench affords exo-mono- and exo,exo-bis-substituted derivatives of Tröger's base in good to excellent yields. The variation of the number of equivalents of s-BuLi/TMEDA and the order of addition of the electrophile strongly govern the outcome of the reaction for each electrophile.
12.	Döllinger, Lillian, et al. (författare) Effectively training emotion recognition accuracy : The evaluation of two systematic training programs 2019 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract This study presents findings about the effectiveness of two computerized training-programs for emotion recognition accuracy that were evaluated in a double-blind randomized controlled study with repeated measures design. Both trainings are effective in training emotion recognition accuracy. The trainings and results are presented in detail and practical implications are discussed.
13.	Ebner, Natalie, et al. (författare) Neuroplasticity and cognitive benefits associated with chronic intranasal oxytocin administration in aging 2019 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Oxytocin (OT) is a crucial chemical modulator of social behavior, and intranasal OT administration has potential as treatment for social deficits. Considerably less is known about OT’s effects on non-social cognition, a functional domain of particular relevance in aging. Brain mechanisms underlying OT’s benefits are not well understood but recent animal work suggests that repeated OT administration induces brain changes. To test this neuroplastic role of OT on the human brain and its potential for cognitive improvement in aging, we conducted a randomized double-blind study in older men (> 56 years), with 34 participants self-administering either 24 IUs OT or placebo (P) twice daily. Before and after 4-weeks intranasal administration, participants underwent MRI and processing speed assessment. Using voxel-based morphometry, gray matter (GM) volume was measured on T1-weighted anatomical images. Age, education, physical health, and image quality served as covariates and family-wise error rate determined statistical significance in regions of interest. Analyses were performed without awareness of the assigned treatment labels. Significant interactions between treatment (OT vs. P) and time (pre- vs. post-intervention) on GM volume for left amygdala, hippocampus, and putamen suggested increased regional GM volume following OT but not P. Further, OT-induced enlargement in putamen was associated with improved processing speed, while there was no brain−behavior correlation in the P group. These findings support the notion that amygdala, hippocampus, and putamen are key targets of OT’s neuroplastic potential on the human brain and chronic OT administration may constitute a potential treatment in counteracting cognitive decline in aging.
14.	Faria, Vanda, et al. (författare) Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder : A Randomized Trial 2017 Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 24, s. 179-188 Tidskriftsartikel (refereegranskat)abstract Background: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety, but their efficacy relative to placebo has been questioned. We aimed to test how manipulation of verbally induced expectancies, central for placebo, influences SSRI treatment outcome and brain activity in patients with social anxiety disorder (SAD).Methods: We did a randomized clinical trial, within an academic medical center (Uppsala, Sweden), of individuals fulfilling the DSM-IV criteria for SAD, recruited through media advertising. Participants were 18 years or older and randomized in blocks, through a computer-generated sequence by an independent party, to nine weeks of overt or covert treatment with escitalopram(20 mg daily). The overt group received correct treatment information whereas the covert group was treated deceptively with the SSRI described, by the psychiatrist, as active placebo. The treating psychiatrist was necessarily unmasked while the research staff was masked from intervention assignment. Treatment efficacy was assessed primarily with the self-rated Liebowitz Social Anxiety Scale (LSAS-SR), administered at week 0, 1, 3, 6 and 9, also yielding a dichotomous estimate of responder status (clinically significant improvement). Before and at the last week of treatment, brain activity during an emotional face-matching task was assessed with functional magnetic resonance imaging (fMRI) and during fMRI sessions, anticipatory speech anxiety was also assessed with the Spielberger State-Trait Anxiety Inventory - State version (STAI-S). Analyses included all randomized patients with outcome data at posttreatment. This study is registered at ISRCTN, number 98890605.Findings: Between March 17th 2014 and May 22nd 2015, 47 patients were recruited. One patient in the covert group dropped out after a few days of treatment and did not provide fMRI data, leaving 46 patients with complete outcome data. After nine weeks of treatment, overt (n = 24) as compared to covert (n = 22) SSRI administration yielded significantly better outcome on the LSAS-SR (adjusted difference 21.17, 95% CI 10.69–31.65, p < 0.0001) with more than three times higher response rate (50% vs. 14%; χ2(1) = 6.91, p = 0.009) and twice the effect size (d = 2.24 vs. d = 1.13) from pre-to posttreatment. There was no significant between-group difference on anticipatory speech anxiety (STAI-S), both groups improving with treatment. No serious adverse reactions were recorded. On fMRI outcomes, there was suggestive evidence for a differential neural response to treatment between groups in the posterior cingulate, superior temporal and inferior frontal gyri (all z thresholds exceeding 3.68, p ≤ 0.001). Reduced social anxiety with treatment correlated significantly with enhanced posterior cingulate (z threshold 3.24, p = 0.0006) and attenuated amygdala (z threshold 2.70, p = 0.003) activity.Interpretation: The clinical and neural effects of escitalopram were markedly influenced by verbal suggestions. This points to a pronounced placebo component in SSRI-treatment of SAD and favors a biopsychosocial over a biomedical explanatory model for SSRI efficacy.
15.	Fischer, Håkan, et al. (författare) Divergent effects of oxytocin in men and women : Increased dorsomedial prefrontal cortex activity to negative emotion displays in men but not in women 2019 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract The neuropeptide oxytocin plays a prominent role in social and emotional cognition. Findings suggest that intranasal oxytocin administration facilitates emotion recognition in humans, but individual and contextual differences may have moderating effects. A major caveat in this line of work is its predominant focus on young males, which limits current knowledge and generalizability across gender. To uncover potential gender effects, the present study included 32 men (mean age 45.78, sd. 22.87) and 39 women (mean 47.87, sd. 22.59). Utilizing a randomized, double-blind, placebo-controlled, within-subjects design, participants self-administered a single-dose of 40 IUs intranasal oxytocin 40 minutes prior to completion of a dynamic emotion recognition task in the MRI scanning. The task paradigm used positive and negative stimuli from the Geneva Multimodal Emotion Portrayals Core Set. Preliminary analyses show that oxytocin induced dorsomedial prefrontal cortex (dmPFC) activity reductions during exposure to negative (relative to positive) stimuli in women, while dmPCF activity was increased under this condition in men. We observed no effect of sex in the behavioral data, however, the results show a similar trend as in brain data. We speculate that the effects of oxytocin on brain activity during emotion recognition may be related to emotion-regulatory and mentalization processes. The observed gender-differential modulatory role of oxytocin raises concern of a bias in the previous oxytocin literature on emotion recognition and associated brain activity by neglecting women in the examination. Next, we will determine the role of age effects on gender-bytreatment interactions, as well as consider modality of the emotion stimulus presentation.
16.	Forsström, David, 1981-, et al. (författare) Isolation and worry in relation to gambling and onset of gambling among psychiatry patients during the COVID-19 pandemic : A mediation study 2022 Ingår i: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 13 Tidskriftsartikel (refereegranskat)abstract When the COVID-19 pandemic started spreading globally, there was a fear that addictive behaviors would increase due to changes in everyday life caused by restrictions due to COVID-19. Studies were carried out to explore if this was true for gambling, typically revealing no overall increase in gambling behavior, although individuals who had previous experience with gambling problems were more likely to increase gambling during the pandemic. However, these studies only included individuals with previous gambling problems. It remains unknown whether other vulnerable groups, such as individuals with common mental disorders increased their gambling. This study aimed to explore the level of gambling problems among individuals with a history of mental disorders, namely, (i) pre-pandemic gamblers and (ii) pandemic-onset gamblers. Furthermore, we explored if worry and isolation mediate gambling and problem gambling. The data were analyzed using descriptive statistics and a structural equation model to investigate mediation. The results showed a high prevalence of at-risk and problem gambling in both groups. The pre-pandemic gamblers had a high level of at-risk and problem gambling. Furthermore, the individuals that started to gamble during the pandemic had an even higher degree of at-risk and problem gambling. The mediation showed that the onset of gambling was linked with the worry of COVID-infection and that worry predicted the level of gambling problems. This study highlights that vulnerability factors, isolation, and worry can be triggers for individuals with common mental disorders to engage in gambling as well as the importance of screening this population for gambling problems.
17.	Frick, Andreas, et al. (författare) Brain changes in social anxiety disorder run in the family 2018 Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 36, s. 5-6 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
18.	Garke, Maria Å., et al. (författare) Improvements in emotion regulation during cognitive behavior therapy predict subsequent social anxiety reductions 2024 Ingår i: Cognitive Behaviour Therapy. - : Routledge. - 1650-6073 .- 1651-2316. Tidskriftsartikel (refereegranskat)abstract Individuals with social anxiety disorder (SAD) experience overall emotion regulation difficulties, but less is known about the long-term role of such difficulties in cognitive behavior therapy (CBT) for SAD. Forty-six patients with SAD receiving internet-delivered CBT, and matched healthy controls (HCs; n = 39), self-reported the Difficulties in Emotion Regulation Scale (DERS), Liebowitz Social Anxiety Scale (LSAS-SR), and participated in anticipatory speech anxiety behavioral experiments. Patients were measured at seven time points before, during and after CBT over a total period of 28 months, and HCs at two timepoints. Disaggregated growth curve models with a total of 263 observations were used, as well as intra-class correlation coefficients and regression models. Patients' LSAS-SR and DERS ratings were reliable (ICC = .83 and .75 respectively), and patients, relative to controls, showed larger difficulties in emotion regulation at pre-treatment (p < .001). During CBT, within-individual improvements in emotion regulation significantly predicted later LSAS-SR reductions (p = .041, pseudo-R2 = 43%). Changes in emotion regulation may thus be important to monitor on an individual level and may be used to improve outcomes in future developments of internet-delivered CBT.
19.	Goodwin, Guy M., et al. (författare) From neuroscience to evidence based psychological treatments - The promise and the challenge, ECNP March 2016, Nice, France 2018 Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 28:2, s. 317-333 Tidskriftsartikel (refereegranskat)abstract This ECNP meeting was designed to build bridges between different constituencies of mental illness treatment researchers from a range of backgrounds with a specific focus on enhancing the development of novel, evidence based, psychological treatments. In particular we wished to explore the potential for basic neuroscience to support the development of more effective psychological treatments, just as this approach is starting to illuminate the actions of drugs. To fulfil this aim, a selection of clinical psychologists, psychiatrists and neuroscientists were invited to sit at the same table. The starting point of the meeting was the proposition that we know certain psychological treatments work, but we have only an approximate understanding of why they work. The first task in developing a coherent mental health science would therefore be to uncover the mechanisms (at all levels of analysis) of effective psychological treatments. Delineating these mechanisms, a task that will require input from both the clinic and the laboratory, will provide a key foundation for the rational optimisation of psychological treatments. As reviewed in this paper, the speakers at the meeting reviewed recent advances in the understanding of clinical and cognitive psychology, neuroscience, experimental psychopathology, and treatment delivery technology focussed primarily on anxiety disorders and depression. We started by asking three rhetorical questions: What has psychology done for treatment? What has technology done for psychology? What has neuroscience done for psychology? We then addressed how research in five broad research areas could inform the future development of better treatments: Attention, Conditioning, Compulsions and addiction, Emotional Memory, and Reward and emotional bias. Research in all these areas (and more) can be harnessed to neuroscience since psychological therapies are a learning process with a biological basis in the brain. Because current treatment approaches are not fully satisfactory, there is an imperative to understand why not. And when psychological therapies do work we need to understand why this is the case, and how we can improve them. We may be able to improve accessibility to treatment without understanding mechanisms. But for treatment innovation and improvement, mechanistic insights may actually help. Applying neuroscience in this way will become an additional mission for ECNP. (C) 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
20.	Groenewold, Nynke A., et al. (författare) Volume of subcortical brain regions in social anxiety disorder : mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group 2023 Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 28:3, s. 1079-1089 Tidskriftsartikel (refereegranskat)abstract There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = −0.077, pFWE = 0.037; right: d = −0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = −0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = −0.141, pFWE < 0.001; right: d = −0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.
21.	Groenewold, Nynke, et al. (författare) Subcortical Volumes in Social Anxiety Disorder : Preliminary Results From Enigma-Anxiety 2018 Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 83:9, s. S247-S248 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
22.	Han, Laura K. M., et al. (författare) Accelerating research on biological aging and mental health : Current challenges and future directions 2019 Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 106, s. 293-311 Tidskriftsartikel (refereegranskat)abstract Aging is associated with complex biological changes that can be accelerated, slowed, or even temporarily reversed by biological and non-biological factors. This article focuses on the link between biological aging, psychological stressors, and mental illness. Rather than comprehensively reviewing this rapidly expanding field, we highlight challenges in this area of research and propose potential strategies to accelerate progress in this field. This effort requires the interaction of scientists across disciplines - including biology, psychiatry, psychology, and epidemiology; and across levels of analysis that emphasize different outcome measures - functional capacity, physiological, cellular, and molecular. Dialogues across disciplines and levels of analysis naturally lead to new opportunities for discovery but also to stimulating challenges. Some important challenges consist of 1) establishing the best objective and predictive biological age indicators or combinations of indicators, 2) identifying the basis for inter-individual differences in the rate of biological aging, and 3) examining to what extent interventions can delay, halt or temporarily reverse aging trajectories. Discovering how psychological states influence biological aging, and vice versa, has the potential to create novel and exciting opportunities for healthcare and possibly yield insights into the fundamental mechanisms that drive human aging.
23.	Hjorth, Olof, et al. (författare) Expression and co-expression of serotonin and dopamine transporters in social anxiety disorder : a multitracer positron emission tomography study 2021 Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:8, s. 3970-3979 Tidskriftsartikel (refereegranskat)abstract Serotonin and dopamine are putatively involved in the etiology and treatment of anxiety disorders, but positron emission tomography (PET) studies probing the two neurotransmitters in the same individuals are lacking. The aim of this multitracer PET study was to evaluate the regional expression and co-expression of the transporter proteins for serotonin (SERT) and dopamine (DAT) in patients with social anxiety disorder (SAD). Voxel-wise binding potentials (BPND) for SERT and DAT were determined in 27 patients with SAD and 43 age- and sex-matched healthy controls, using the radioligands [11C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile) and [11C]PE2I (N-(3-iodopro-2E-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)nortropane). Results showed that, within transmitter systems, SAD patients exhibited higher SERT binding in the nucleus accumbens while DAT availability in the amygdala, hippocampus, and putamen correlated positively with symptom severity. At a more lenient statistical threshold, SERT and DAT BPND were also higher in other striatal and limbic regions in patients, and correlated with symptom severity, whereas no brain region showed higher binding in healthy controls. Moreover, SERT/DAT co-expression was significantly higher in SAD patients in the amygdala, nucleus accumbens, caudate, putamen, and posterior ventral thalamus, while lower co-expression was noted in the dorsomedial thalamus. Follow-up logistic regression analysis confirmed that SAD diagnosis was significantly predicted by the statistical interaction between SERT and DAT availability, in the amygdala, putamen, and dorsomedial thalamus. Thus, SAD was associated with mainly increased expression and co-expression of the transporters for serotonin and dopamine in fear and reward-related brain regions. Resultant monoamine dysregulation may underlie SAD symptomatology and constitute a target for treatment.
24.	Hjorth, Olof, et al. (författare) Response expectancies shape the effect of SSRI treatment on serotonin and dopamine transporters in patients with social anxiety disorder Annan publikation (övrigt vetenskapligt/konstnärligt)
25.	Ivanov, Volen Z., et al. (författare) Enhancing group cognitive-behavioral therapy for hoarding disorder with between-session Internet-based clinician support : A feasibility study 2018 Ingår i: Journal of Clinical Psychology. - : Wiley. - 0021-9762 .- 1097-4679. ; 74:7, s. 1092-1105 Tidskriftsartikel (refereegranskat)abstract Objective Hoarding disorder (HD) is difficult to treat. In an effort to increase efficacy and engagement in cognitive-behavioral therapy (CBT), we developed and evaluated a novel intervention comprising group CBT combined with between-session Internet-based clinician support for people with HD.Method Twenty participants with HD received group CBT combined with an Internet-support system enabling therapist-participant communication between group sessions.Results The treatment was associated with a significant reduction on the Saving InventoryRevised (SI-R) and a large effect size (Cohen's d=1.57) was found at posttreatment. Treatment gains were maintained at the 3-month follow-up. Group attendance was high and no participants dropped out from treatment prematurely. Between-session motivational support from the therapist was most frequently mentioned as the main strength of the system.Conclusion The results of this study support adding Internet-based clinician support to group CBT for HD to increase treatment adherence and, potentially, improve the overall efficacy of CBT.
26.	Koenig, Julian, et al. (författare) Cortical thickness and resting-state cardiac function across the lifespan : A cross-sectional pooled mega-analysis 2021 Ingår i: Psychophysiology. - : Wiley. - 0048-5772 .- 1469-8986 .- 1540-5958. ; 58:7 Tidskriftsartikel (refereegranskat)abstract Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12–87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS—or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
27.	Kraepelien, Martin, et al. (författare) Individually Tailored Internet-Based Cognitive-Behavioral Therapy for Daily Functioning in Patients with Parkinsons Disease : A Randomized Controlled Trial 2020 Ingår i: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 10:2, s. 653-664 Tidskriftsartikel (refereegranskat)abstract Background: Parkinson's disease (PD) is often associated with psychological distress and lowered daily functioning. The availability of psychological interventions tailored for people with Parkinson is very limited. Objective: To study if guided individually-tailored internet-based cognitive behavioral therapy (ICBT) provide additional value to standard medical treatment for PD. Methods: Seventy-seven individuals with PD and self-reported problems with general function measured with the Work and Social Adjustment Scale (WSAS > 15) were randomized to 10 weeks of either ICBT combined with standard medical treatment, or standard medical treatment plus being on waitlist to ICBT (CONTROL). Change in the main outcome WSAS, as well as secondary measures such as quality of life, depression, anxiety and insomnia symptoms were investigated post treatment. Results: Participants receiving ICBT reported significantly higher functioning after treatment (WSAS group difference -4.56, controlled effect size g = 0.69, significant group by time interaction, W.2 = 26.23, p = 0.001). However, only around one third of participants in the treatment group were classified as treatment responders, defined as having a 30% reduction on the WSAS post treatment. Patient involvement and ratings of ICBT credibility were high. Symptoms of anxiety, depression and insomnia symptoms were significantly lower after treatment compared to CONTROL. There were also positive effects on Parkinson-specific function and quality of life in the treatment group. Conclusions: ICBT as an addition to standard medical treatment was credible and improved functioning for some individuals with PD. Still, the treatment needs further development in order to help a larger proportion of individuals with PD. Trial registration number: ClinicalTrials.gov NCT02627885.
28.	Laplante.Lévesque, Ariane, et al. (författare) An online information transfer support system for audiologists and their first-time hearing aid clients 2014 Konferensbidrag (övrigt vetenskapligt/konstnärligt)
29.	Laukka, Petri, et al. (författare) Neural correlates of individual differences in emotion recognition ability : an fMRI study 2019 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract The ability to understand how others are feeling is important for social interaction. Studies have reported large inter-individual variability in emotion recognition ability (ERA) in the general population, but the causes for such differences are not well understood. This study investigated neural response during emotion recognition in individuals with high and low ERA. Forty-nine young adults were selected for inclusion based on their performance during previous testing of ERA (e.g., Hovey et al., 2018, Soc Cogn Affect Neurosci, 13, 173-181). Neural response was determined using the blood-oxygen level-dependent (BOLD) signal in a 3-Tesla functional magnetic resonance imaging (fMRI) experiment. The participants were asked to judge which emotions (anger, fear, disgust, happiness, interest, pride, relief, sadness, and neutral expression) were demonstrated in brief clips (i.e. audio-only, video-only, and multimodal audio- video) using a forced-choice response format. Stimuli were taken from the GEMEP emotion portrayal database (Bänziger et al., 2009, Emotion, 9, 691-704). In neural response to emotional stimuli, individuals with high ERA, relative to low ERA, showed higher activation bilaterally in the supplementary motor area, and in the left postcentral gyrus. Results provide initial evidence that the ability to effectively recognize the emotions of others is related to motor and somatosensory neural responses. We speculate that these neural responses in individuals with improved skills in emotion recognition could be related to increased embodiment of emotion expressions during emotion perception.
30.	Laukka, Petri, 1971-, et al. (författare) Neural correlates of individual differences in multimodal emotion recognition ability 2024 Ingår i: Cortex. - : Elsevier. - 0010-9452 .- 1973-8102. ; 175, s. 1-11 Tidskriftsartikel (refereegranskat)abstract Studies have reported substantial variability in emotion recognition ability (ERA) – an important social skill – but possible neural underpinnings for such individual differences are not well understood. This functional magnetic resonance imaging (fMRI) study investigated neural responses during emotion recognition in young adults (N=49) who were selected for inclusion based on their performance (high or low) during previous testing of ERA. Participants were asked to judge brief video recordings in a forced-choice emotion recognition task, wherein stimuli were presented in visual, auditory and multimodal (audiovisual) blocks. Emotion recognition rates during brain scanning confirmed that individuals with high (vs. low) ERA received higher accuracy for all presentation blocks. fMRI-analyses focused on key regions of interest (ROIs) involved in the processing of multimodal emotion expressions, based on previous meta-analyses. In neural response to emotional stimuli contrasted with neutral stimuli, individuals with high (vs. low) ERA showed higher activation in the following ROIs during the multimodal condition: right middle superior temporal gyrus (mSTG), right posterior superior temporal sulcus (PSTS), and right inferior frontal cortex (IFC). Overall, results suggest that individual variability in ERA may be reflected across several stages of decisional processing, including extraction (mSTG), integration (PSTS) and evaluation (IFC) of emotional information.
31.	Lenhard, Fabian, et al. (författare) Prediction of outcome in internet-delivered cognitive behaviour therapy for paediatric obsessive-compulsive disorder : A machine learning approach 2018 Ingår i: International Journal of Methods in Psychiatric Research. - : Wiley. - 1049-8931 .- 1557-0657. ; 27:1 Tidskriftsartikel (refereegranskat)abstract Background: There are no consistent predictors of treatment outcome in paediatric obsessive–compulsive disorder (OCD). One reason for this might be the use of suboptimal statistical methodology. Machine learning is an approach to efficiently analyse complex data. Machine learning has been widely used within other fields, but has rarely been tested in the prediction of paediatric mental health treatment outcomes.Objective: To test four different machine learning methods in the prediction of treatment response in a sample of paediatric OCD patients who had received Internet-delivered cognitive behaviour therapy (ICBT).Methods: Participants were 61 adolescents (12–17 years) who enrolled in a randomized controlled trial and received ICBT. All clinical baseline variables were used to predict strictly defined treatment response status three months after ICBT. Four machine learning algorithms were implemented. For comparison, we also employed a traditional logistic regression approach.Results: Multivariate logistic regression could not detect any significant predictors. In contrast, all four machine learning algorithms performed well in the prediction of treatment response, with 75 to 83% accuracy.Conclusions: The results suggest that machine learning algorithms can successfully be applied to predict paediatric OCD treatment outcome. Validation studies and studies in other disorders are warranted.
32.	Li, Xia, et al. (författare) A Quantitative Data-Driven Analysis Framework for Resting-State Functional Magnetic Resonance Imaging : A Study of the Impact of Adult Age 2021 Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 15 Tidskriftsartikel (refereegranskat)abstract The objective of this study is to introduce a new quantitative data-driven analysis (QDA) framework for the analysis of resting-state fMRI (R-fMRI) and use it to investigate the effect of adult age on resting-state functional connectivity (RFC). Whole-brain R-fMRI measurements were conducted on a 3T clinical MRI scanner in 227 healthy adult volunteers (N = 227, aged 18–76 years old, male/female = 99/128). With the proposed QDA framework we derived two types of voxel-wise RFC metrics: the connectivity strength index and connectivity density index utilizing the convolutions of the cross-correlation histogram with different kernels. Furthermore, we assessed the negative and positive portions of these metrics separately. With the QDA framework we found age-related declines of RFC metrics in the superior and middle frontal gyri, posterior cingulate cortex (PCC), right insula and inferior parietal lobule of the default mode network (DMN), which resembles previously reported results using other types of RFC data processing methods. Importantly, our new findings complement previously undocumented results in the following aspects: (1) the PCC and right insula are anti-correlated and tend to manifest simultaneously declines of both the negative and positive connectivity strength with subjects’ age; (2) separate assessment of the negative and positive RFC metrics provides enhanced sensitivity to the aging effect; and (3) the sensorimotor network depicts enhanced negative connectivity strength with the adult age. The proposed QDA framework can produce threshold-free and voxel-wise RFC metrics from R-fMRI data. The detected adult age effect is largely consistent with previously reported studies using different R-fMRI analysis approaches. Moreover, the separate assessment of the negative and positive contributions to the RFC metrics can enhance the RFC sensitivity and clarify some of the mixed results in the literature regarding to the DMN and sensorimotor network involvement in adult aging.
33.	Li, Xia, et al. (författare) Dataset of whole-brain resting-state fMRI of 227 young and elderly adults acquired at 3T 2021 Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 38 Tidskriftsartikel (refereegranskat)abstract To investigate the impact of adult age on the brain functional connectivity, whole-brain resting-state functional magnetic resonance imaging (R-fMRI) data were acquired on a 3T clinical MRI scanner in a cohort of 227, right-handed, native Swedish-speaking, healthy adult volunteers (N=227, aged 18-74 years old, male/female=99/128). The dataset is mainly consisted of a younger (18-30 years old n=124, males/females=51/73) and elderly adult (n=76, 60-76 years old, males/females=35/41) subgroups. The dataset was analyzed using a new data-driven analysis (QDA) framework. With QDA two types of threshold-free voxel-wise resting-state functional connectivity (RFC) metrics were derived: the connectivity strength index (CSI) and connectivity density index (CDI), which can be utilized to assess the brain changes in functional connectivity associated with adult age. The dataset can also be useful as a reference to identify abnormal changes in brain functional connectivity resulted from neurodegenerative or neuropsychiatric disorders.
34.	Lindahl, Jesper, et al. (författare) Add-on pramipexole for anhedonic depression : study protocol for a randomised controlled trial and open-label follow-up in Lund, Sweden 2023 Ingår i: BMJ Open. - : BMJ Publishing Group. - 2044-6055. ; 13:11, s. 9 Tidskriftsartikel (refereegranskat)abstract INTRODUCTION: Many depressed patients do not achieve remission with available treatments. Anhedonia is a common residual symptom associated with treatment resistance as well as low function and quality of life. There are currently no specific and effective treatments for anhedonia. Some trials have shown that dopamine agonist pramipexole is efficacious for treating depression, but more data is needed before it could become ready for clinical prime time. Given its mechanism of action, pramipexole might be a useful treatment for a depression subtype characterised by significant anhedonia and lack of motivation-symptoms associated with dopaminergic hypofunction. We recently showed, in an open-label pilot study, that add-on pramipexole is a feasible treatment for depression with significant anhedonia, and that pramipexole increases reward-related activity in the ventral striatum. We will now confirm or refute these preliminary results in a randomised controlled trial (RCT) and an open-label follow-up study. METHODS AND ANALYSIS: Eighty patients with major depression (bipolar or unipolar) or dysthymia and significant anhedonia according to the Snaith Hamilton Pleasure Scale (SHAPS) are randomised to either add-on pramipexole or placebo for 9 weeks. Change in anhedonia symptoms per the SHAPS is the primary outcome, and secondary outcomes include change in core depressive symptoms, apathy, sleep problems, life quality, anxiety and side effects. Accelerometers are used to assess treatment-associated changes in physical activity and sleep patterns. Blood and brain biomarkers are investigated as treatment predictors and to establish target engagement. After the RCT phase, patients continue with open-label treatment in a 6-month follow-up study aiming to assess long-term efficacy and tolerability of pramipexole. ETHICS AND DISSEMINATION: The study has been approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. The study is externally monitored according to Good Clinical Practice guidelines. Results will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05355337 and NCT05825235.
35.	Lindqvist, Daniel, et al. (författare) Plasma circulating cell-free mitochondrial DNA in social anxiety disorder 2022 Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 148 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To investigate plasma levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in patients with social anxiety disorder (SAD) and healthy controls (HC).METHODS: In this study, 88 participants (46 patients with SAD and 42 HCs) were enrolled and both ccf-mtDNA and peripheral blood mononuclear cells (PBMC) mtDNA copy number (mtDNA-cn) were measured at up to three times per individual (9-11 weeks apart). SAD patients also received cognitive behavioral therapy (CBT) between the second and third time-point.RESULTS: SAD patients had significantly lower ccf-mtDNA compared to HCs at all time points, but ccf-mtDNA did not change significantly after CBT, and was not associated with severity of anxiety symptoms. Plasma ccf-mtDNA did not significantly correlate with PBMC mtDNA-cn in patients.CONCLUSION: This is the first report of lower ccf-mtDNA in patients with an anxiety disorder. Our findings could reflect a more chronic illness course in SAD patients with prolonged periods of psychological stress leading to decreased levels of ccf-mtDNA, but future longitudinal studies are needed to confirm or refute this hypothesis.
36.	Lussier, Desiree, et al. (författare) Four-week Intranasal Oxytocin vs Placebo Administration Modulation of Amygdala and Accumbens Volume 2018 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Introduction: Gray matter (GM) volumes of limbic and striatal structures, including the amygdala (AMY)1 and the nucleus accumbens (NAcc)2, are associated with socioemotional phenotypes. For instance, GM atrophy accompanies some dementias in which socioemotional processing is impaired2,3. Evidence suggests that intranasally administered oxytocin (OT) exerts a modulatory effect on socioemotional processing4, with the AMY5,6 and NAcc7 constituting strong potential targets for this in the brain modulatory process. There, further, is evidence that AMY volume is associated with endogenous OT levels in young adults8. However, the generalizability of this finding to older adults is currently unknown. Additionally, literature describing the effects of long-term OT administration on the aging brain is lacking.Methods: Twenty-four healthy male participants, aged 55 years and older, were randomly assigned in a double-blind design to self-administer intranasally either 24IUs of OT or placebo (P) twice daily for four weeks as part of an ongoing clinical trial conducted at the University of Florida. A structural T1-weighted magnetization prepared rapid gradient-echo (MPRAGE) (1 mm3 isotropic voxels) scan was acquired at baseline and again posttreatment using a 3T Phillips scanner with a 32-channel head coil. Freesurfer was used for whole-brain structural segmentation9. Subcortical segmentation statistics (aseg.stat) volumetrics were extracted and analyses were conducted with Rstudio. The Stats10 package for R was used to run paired t-tests within each of the two treatment conditions (OT vs. P) to determine volume changes in amygdala and nucleus accumbens pre- to post-treatment. All analyses were conducted blind to the experimental conditions. Unblinding will be undertaken prior to the presentation of the final results.Results: T-tests resulted in a significant increase in bilateral NAcc GM volume for one (t = -5.60, df = 12, p-value < 0.001 left; t = -4.2851, df = 12, p-value = 0.001 right) but not in the other (t = -1.58, df = 10, p-value = 0.149 left; t = t = -1.78, df = 10, p-value = 0.105 right) treatment condition. Additionally, there was a trend-wise decrease in total GM volume from pre- to post-treatment in the right AMY in one (t = 3.20, df = 12, p-value = 0.008) but not in the other (t = 0.89, df = 10, p-value = 0.396) treatment condition. However, this observation was reversed for the left AMY (t = 1.130, df = 12, p-value = 0.280 and t = 3.2065, df = 10, p-value = 0.009, respectively).Conclusions: The results of this project suggest that 4-week intranasal OT vs. P administration differentially modulates brain volume in AMY and NAcc in healthy older men, with these modulatory effects possibly lateralized for the AMY. These findings are in line with previous literature showing that there may be hemispheric differences in socioemotional task-related AMY activation. Future extensions of this work will include a larger sample size to confirm the robustness of the findings and investigation into associations with socioemotional functioning.
37.	Månsson, Kristoffer, et al. (författare) Affective Brain Signal Variability Separates Social Anxiety Disorder Patients From Healthy Individuals 2018 Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 83:9, s. S249-S250 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Background: Amygdala hyper-responsiveness to negative socio-affective stimuli have typically been demonstrated in patients with social anxiety disorder (SAD). Relative to conventional methods, there is emerging evidence that brain signal variability could be a better predictor of behavior than mean neural response.Methods: We recruited 46 patients with SAD (mean age 31, 63% females) and 40 matched healthy controls (HC) to undergo 3 Tesla functional magnetic resonance imaging (fMRI) at 2 time-points, totaling 172 MRIsessions. Blood-oxygen level-dependent (BOLD-fMRI) was performed while viewing happy and fearful faces in blocks of 80 seconds. BOLD-fMRI data was reviewed by manually classifying signal from noise. Variability was calculated as each voxel’s standard deviation on signal across scanning-time. Multivariate partial least squares (PLS) estimated patterns of variability that separates patient from controls.Results: PLS found one significant latent variable with cross-block covariance on 64%, permutated (x 1000) P<0.001, bootstrapped 95% confidence intervals on each condition, demonstrating less signal variability to happy faces in patients, relative to controls. This pattern of response was spatially located in several regions across the whole-brain, with large clusters appearing in bilateral amygdala, medial prefrontal cortex and posterior cingulate cortex/precuneus.Conclusions: We found that neural response variability to positive socio-affective stimuli accurately separated patients from controls. It is likely that less signal variability highlights a deficit in effective emotion processing. We add to the growing literature on healthy individuals suggesting that task-specific brain signal variability contains useful information. The brain signal variability approach opens new avenues to evaluate and better understand brain function in common psychopathology.
38.	Månsson, Kristoffer, et al. (författare) Brain Before Behavior : Temporal Dynamics in the Treatment of Social Anxiety - Neural Changes Occur Early and Precede Clinical Improvement 2018 Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 83:9, s. S130-S131 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Background: The brain rapidly responds to affective processing and neural responsivity can separate anxiety disorder patients from healthy individuals. Psychiatric treatment also alters brain responsiveness however, the brain’s temporal dynamics during treatment remain unknown. Here, patients with social anxiety disorder (SAD) were treated with cognitive-behavioral therapy (CBT) and functional magnetic resonance imaging (fMRI) assessments were performed before, during and after intervention.Methods: Forty-six SAD patients received a 9-week Internet-delivered CBTand symptoms were assessed weekly using the Liebowitz social anxiety scale (LSAS-SR). MRI was acquired at 4 time-points (2 baselines, mid- and post-treatment). Blood-oxygen level-dependent(BOLD-fMRI) was performed while patients viewed negative facial expressions. BOLD-fMRI data was reviewed manually by classifying signal from noise, all subjects contributing with complete data.Results: Patients improved slightly from baseline to mid-treatment (P<.001, Cohen’s d=0.34) on the LSAS-SR, but more so from mid- to post-treatment (P<.001, d=1.46). Whole-brain neural responsivity decreased from baseline to post-treatment (False Discovery Rate, FDR P<.005) in the medial prefrontal cortex, precuneus and amygdala/parahippocampus. However, no changes (FDR P>.05) from mid- to post-treatment were found, suggesting that the early alterations accounted for the effect. Furthermore, early response reductions were positively associated with symptom improvement from pre-post treatment (Pearson’s r=.50, P<.001).Conclusions: This is, to our knowledge, the first study assessing early and late psychiatric treatment changes in the brain. Interestingly, altered neural responsivity in limbic and default-mode network regions preceded self-reported alleviation of social anxiety. Understanding the brain’s temporal dynamics and subsequent modification of behavior may be highly important for future clinical neuroimaging research.
39.	Månsson, Kristoffer, et al. (författare) Brain Signal Variability and Indices of Cellular Protection Predicts Social Anxiety Disorder Treatment Outcome 2019 Ingår i: Proceedings of the 9th World Congress of Behavioural & Cognitive Therapies. - Tübingen : dgvt-Verlag. - 9783871598517 ; , s. 158-158 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract We are currently lacking clinically useful predictors of treatment response in common psychiatric disorders. Non-invasive and increasingly accessible neuroimaging techniques like functional magnetic resonance imaging (fMRI) could be a useful tool. In contrast to the conventional approach investigating the brain’s average responses, the brain’s signal variability could be a better estimate of the brain’s dynamic operations (Garrett et al., 2010, 2015). In addition, telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, we investigate if baseline BOLD-fMRI signal variability, and indices of cellular protection, predicts social anxiety disorder patient’s response to internet-delivered cognitive behavior therapy. Forty-six patients with social anxiety disorder (SAD) were scanned twice with a 3 Tesla fMRI before initiating CBT. Treatment outcome was assessed the Liebowitz Social Anxiety Scale (self-report). 1) BOLD-fMRI acquisition was performed while passively viewing emotional faces flashing on the screen for 80 seconds. Raw BOLD-fMRI data was implemented in an Independent Component Analysis in order to manually denoise images by carefully remove noise from neural signal. Across time, each voxel’s standard deviation was calculated and used as an index of variability. Multivariate partial least squares regression models were used for second level analysis. 2) Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. Significant latent level brain scores, and baseline analytes were implemented in linear regressions with LSAS-SR change score as the outcome. Results will be presented and discussed.
40.	Månsson, Kristoffer, et al. (författare) Can Psychological Treatment Slow Down Cellular Aging in Social Anxiety Disorder? : An Intervention Study Evaluating Changes in Telomere Length and Telomerase Activity 2018 Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 83:9, s. S351-S352 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Background: Mental illness, including anxiety disorders, is linked to accelerated cell aging. This is evidenced by shorter leukocyte telomere length. Cells with critically short telomeres may undergo apoptosis. In dividing cells, telomere shortening is counteracted by the telomeraseenzyme. Telomerase is reportedly low following chronic psychological stress. We hypothesized that a psychological treatment may increase telomerase activity, less telomere attritionand greater symptom improvement.Methods: Forty-six patients (91% SSRI naïve) with social anxiety disorder(SAD; mean age 31, 63% females) underwent a 9-week waiting period, and 9 weeks of Internet-delivered cognitive behavior therapy(CBT). During treatment, symptoms were assessed weekly using the Liebowitz Social Anxiety Scale (LSAS-SR). Fasting blood samples were collected twice before treatment, and at post-treatment. Genomic DNA was extracted using DNeasy® Blood & Tissue Kit (Qiagene) to assess leukocyte telomere length. Telomerase activity was detected by real-time telomeric repeat amplification protocol (RT-TRAP).Results: Patients improved significantly on the LSAS-SR (p<.001; Cohen’s d=1.5). Pre-post changes in telomerase and telomere length correlated positively (Pearson’s r=.31, p=.05). Reduced telomerase activity (<33th percentile) was associated with less improvement and increased activity (>66th percentile) with more improvement on the LSAS-SR (Z=-2.4, p=.02).Conclusions: We demonstrate, to our knowledge for the first time, that altered telomerase activity is associated with clinical response to a psychological treatment in a psychiatric population. The observed CBT effect on telomerase in patients with SAD is consistent with results from animal trials and a small previous study of antidepressants in humans. Thus, telomerase activation may play an important role in clinical recovery.
41.	Månsson, Kristoffer, et al. (författare) Moment-To-Moment Variability in the Visual Cortex Robustly Predicts Response to Psychological Treatment in Anxiety Disordered Patients 2020 Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 87:9, Supplement Tidskriftsartikel (refereegranskat)abstract Background: There is considerable inter-individual variability in the response to treatment in psychiatric patients. Tools in translational neuroscience, e.g., functional magnetic resonance imaging (fMRI), may be helpful in predicting treatment outcome. Blood-oxygen level-dependent (BOLD) variability, e.g., voxel-wise SD-BOLD, has emerged as an alternative and promising approach for understanding human cognition, but has rarely been considered as a marker of clinical outcome.Methods: Forty-six patients with social anxiety disorder were scanned with 3T BOLD-fMRI twice (9 weeks apart) prior to treatment. In each scanning session, patients passively viewed facial expressions for 160 seconds. After baseline scanning, patients underwent cognitive behavioral therapy (CBT) for 9 weeks. Multivariate partial least squares (PLS) models were used to link SD-BOLD to treatment outcome (anxiety pre-post change scores), and latent level brain scores were implemented in several subsequent linear regression models.Results: Treatment outcome varied across patients, but yielded a large effect on anxiety symptom improvement (Cohen’s d = 1.5) on a group-level. Behavioral PLS models strongly revealed lower visual cortex SD-BOLD in patients with more favorable treatment outcomes (first session: ß=.77, Adj-R2 =.58; and second session ß=.78, Adj-R2 =.60). K-fold cross-validation further supported our results, demonstrating a 60-70% reduction in model out-of-sample prediction error when SD-BOLD was included as a predictor.Conclusions: Our findings provide the first evidence that moment-to-moment variability in neural responses shows translational potential by accurately predicting treatment outcomes in psychiatric patients. If replicated, brain signal variability-based prediction may provide an efficient and viable future tool in clinical psychiatry.
42.	Månsson, Kristoffer NT, et al. (författare) Conventional Cognitive Behavioral Therapy Facilitated by an Internet-Based Support System : Feasibility Study at a Psychiatric Outpatient Clinic. 2017 Ingår i: JMIR Research Protocols. - : J M I R Publications. - 1929-0748. ; 6:8 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Cognitive behavioral therapies have been shown to be effective for a variety of psychiatric and somatic disorders, but some obstacles can be noted in regular psychiatric care; for example, low adherence to treatment protocols may undermine effects. Treatments delivered via the Internet have shown promising results, and it is an open question if the blend of Internet-delivered and conventional face-to-face cognitive behavioral therapies may help to overcome some of the barriers of evidence-based treatments in psychiatric care.OBJECTIVE: We evaluated the feasibility of an Internet-based support system at an outpatient psychiatric clinic in Sweden. For instance, the support system made it possible to send messages and share information between the therapist and the patient before and after therapy sessions at the clinic.METHODS: Nine clinical psychologists participated and 33 patients were enrolled in the current study. We evaluated the usability and technology acceptance after 12 weeks of access. Moreover, clinical data on common psychiatric symptoms were assessed before and after the presentation of the support system.RESULTS: In line with our previous study in a university setting, the Internet-based support system has the potential to be feasible also when delivered in a regular psychiatric setting. Notably, some components in the system were less frequently used. We also found that patients improved on common outcome measures for depressive and anxious symptoms (effect sizes, as determined by Cohen d, ranged from 0.20-0.69).CONCLUSIONS: This study adds to the literature suggesting that modern information technology could be aligned with conventional face-to-face services.
43.	Månsson, Kristoffer N T, et al. (författare) Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder 2013 Ingår i: Psychiatry Research. - : Elsevier BV. - 0925-4927 .- 1872-7506 .- 0165-1781 .- 1872-7123. ; 214:3, s. 229-237 Tidskriftsartikel (refereegranskat)abstract Randomized controlled trials have yielded promising results for internet-delivered cognitive behavior therapy (iCBT) for patients with social anxiety disorder (SAD). The present study investigated anxiety-related neural changes after iCBT for SAD. The amygdala is a critical hub in the neural fear network, receptive to change using emotion regulation strategies and a putative target for iCBT. Twenty-two subjects were included in pre- and post-treatment functional magnetic resonance imaging at 3T assessing neural changes during an affective face processing task. Treatment outcome was assessed using social anxiety self-reports and the Clinical Global Impression-Improvement (CGI-I) scale. ICBT yielded better outcome than ABM (66% vs. 25% CGI-I responders). A significant differential activation of the left amygdala was found with relatively decreased reactivity after iCBT. Changes in the amygdala were related to a behavioral measure of social anxiety. Functional connectivity analysis in the iCBT group showed that the amygdala attenuation was associated with increased activity in the medial orbitofrontal cortex and decreased activity in the right ventrolateral and dorsolateral (dlPFC) cortices. Treatment-induced neural changes with iCBT were consistent with previously reported studies on regular CBT and emotion regulation in general.
44.	Månsson, Kristoffer N. T., et al. (författare) Amygdala Changes After Cognitive Behavior Therapy and Attention Bias Modification via the Internet - An fMRI-Study 2013 Ingår i: Biological Psychiatry. - New York, NY, USA : Elsevier. - 0006-3223 .- 1873-2402. ; 73:9 Supplement, s. 72S-72S Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
45.	Månsson, Kristoffer N. T., et al. (författare) Anterior insula morphology and vulnerability to psychopathology-related symptoms in response to acute inflammation 2022 Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 99, s. 9-16 Tidskriftsartikel (refereegranskat)abstract Introduction: The role of inflammation in common psychiatric diseases is now well acknowledged. However, the factors and mechanisms underlying inter-individual variability in the vulnerability to develop psychopathology related symptoms in response to inflammation are not well characterized. Herein, we aimed at investigating morphological brain regions central for interoception and emotion regulation, and if these are associated with acute inflammation-induced sickness and anxiety responses.Methods: Systemic inflammation was induced using an intravenous injection of lipopolysaccharide (LPS) at a dose of 0.6 ng/kg body weight in 28 healthy individuals, while 21 individuals received an injection of saline (placebo). Individuals' gray matter volume was investigated by automated voxel-based morphometry technique on T1-weighted anatomical images derived from magnetic resonance imaging (MRI). Plasma concentrations of TNF alpha and IL-6, sickness symptoms (SicknessQ), and state anxiety (STAI-S) were measured before and after the injection.Results: A stronger sickness response to LPS was significantly associated with a larger anterior insula gray matter volume, independently from increases in cytokine concentrations, age, sex and body mass index (R-2 = 65.6%). Similarly, a greater LPS-induced state anxiety response was related to a larger anterior insula gray matter volume, and also by a stronger increase in plasma TNF-alpha concentrations (R-2 = 40.4%).Discussion: Anterior insula morphology appears central in the sensitivity to develop symptoms of sickness and anxiety in response to inflammation, and could thus be one risk factor in inflammation-related psychopathologies. Because of the limited sample size, the current results need to be replicated.
46.	Månsson, Kristoffer N T, et al. (författare) Development and Initial Evaluation of an Internet-Based Support System for Face-to-Face Cognitive Behavior Therapy: A Proof of Concept Study 2013 Ingår i: Journal of Medical Internet Research. - : Journal of Medical Internet Research / JMIR Publications. - 1438-8871. ; 15:12 Tidskriftsartikel (refereegranskat)abstract Background: Evidence-based psychological treatments, such as cognitive behavior therapy (CBT), have been found to be effective in treating several anxiety and mood disorders. Nevertheless, issues regarding adherence are common, such as poor patient compliance on homework assignments and therapists drifting from strictly evidence-based CBT. The development of Internet-delivered CBT (ICBT) has been intensive in the past decade and results show that guided ICBT can be as effective as face-to-face CBT but also indicate a need to integrate the two forms of CBT delivery. less thanbrgreater than less thanbrgreater thanObjective: In this study, we developed and tested a new treatment format in which ICBT and face-to-face therapy were blended. We designed a support system accessible via the Internet (using a computer or an Apple iPad) for patients and therapists delivering CBT face-to-face. The support system included basic CBT components and a library of interventions gathered from existing ICBT manuals. less thanbrgreater than less thanbrgreater thanMethods: The study involved 15 patients with mild to moderate anxiety or depression (or both). Eight therapists conducted the treatments. All participants were interviewed after the nine-week intervention. Further, patients provided self-reports on clinical measures pre- and post-trial, as well as at a 12-month follow-up. less thanbrgreater than less thanbrgreater thanResults: A reduction was found in symptom scores across all measures. The reliable change index ranged from 60% to 87% for depression and anxiety. Large effect sizes (Cohens d) ranging from 1.62 (CI 95% 0.59-2.66) to 2.43 (CI 95% 1.12-3.74) were found. There were no missing data and no treatment dropouts. In addition, the results had been maintained at the 12-month follow-up. Qualitative interviews revealed that the users perceived the support system as beneficial. less thanbrgreater than less thanbrgreater thanConclusions: The results suggest that modern information technology can effectively blend with face-to-face treatments and be used to facilitate communication and structure in therapy, thus reducing therapist drift.
47.	Månsson, Kristoffer N. T., et al. (författare) Enriching CBT by Neuroscience : Novel Avenues to Achieve Personalized Treatments 2021 Ingår i: International Journal of Cognitive Therapy. - : Springer. - 1937-1209 .- 1937-1217. ; 14, s. 182-195 Tidskriftsartikel (refereegranskat)abstract Although cognitive behavioral therapy (CBT) is an established and efficient treatment for a variety of common mental disorders, a considerable number of patients do not respond to treatment or relapse after successful CBT. Recent findings and approaches from neuroscience could pave the way for clinical developments to enhance the outcome of CBT. Herein, we will present how neuroscience can offer novel perspectives to better understand (a) the biological underpinnings of CBT, (b) how we can enrich CBT with neuroscience-informed techniques (augmentation of CBT), and (c) why some patients may respond better to CBT than others (predictors of therapy outcomes), thus paving the way for more personalized and effective treatments. We will introduce some key topics and describe a selection of findings from CBT-related research using tools from neuroscience, with the hope that this will provide clinicians and clinical researchers with a brief and comprehensible overview of the field.
48.	Månsson, Kristoffer N. T., et al. (författare) Improvement in indices of cellular protection after psychological treatment for social anxiety disorder 2019 Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1 Tidskriftsartikel (refereegranskat)abstract Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen’s d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.
49.	Månsson, Kristoffer N. T., et al. (författare) Moment-to-Moment Brain Signal Variability Reliably Predicts Psychiatric Treatment Outcome 2022 Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:7, s. 658-666 Tidskriftsartikel (refereegranskat)abstract Background: Biomarkers of psychiatric treatment response remain elusive. Functional magnetic resonance imaging (fMRI) has shown promise, but low reliability has limited the utility of typical fMRI measures (e.g., average brain signal) as harbingers of treatment success. Notably, although historically considered a source of noise, temporal brain signal variability continues to gain momentum as a sensitive and reliable indicator of individual differences in neural efficacy, yet has not been examined in relation to psychiatric treatment outcomes.Methods: A total of 45 patients with social anxiety disorder were scanned twice (11 weeks apart) using simple task-based and resting-state fMRI to capture moment-to-moment neural variability. After fMRI test-retest, patients underwent a 9-week cognitive behavioral therapy. Multivariate modeling and reliability-based cross-validation were used to perform brain-based prediction of treatment outcomes.Results: Task-based brain signal variability was the strongest contributor in a treatment outcome prediction model (total rACTUAL,PREDICTED = 0.77), outperforming self-reports, resting-state neural variability, and standard mean-based measures of neural activity. Notably, task-based brain signal variability showed excellent test-retest reliability (intraclass correlation coefficient = 0.80), even with a task length less than 3 minutes long.Conclusions: Rather than a source of undesirable noise, moment-to-moment fMRI signal variability may instead serve as a highly reliable and efficient prognostic indicator of clinical outcome.
50.	Månsson, Kristoffer N.T., et al. (författare) Multi-voxel Patterns in Fear Network Regions Predict Clinical Outcome One-year after Cognitive Behavior Therapy for Social Anxiety Disorder : A Support Vector Machine fMRI Study 2014 Ingår i: Biological Psychiatry. - : Elsevier. ; , s. 83S-84S Konferensbidrag (refereegranskat)abstract Background: Cognitive behavioral therapy (CBT) has yielded robust treatment effects for social anxiety disorder (SAD) but still many patients do not respond fully to treatment, and a substantial proportion relapse after treatment has ended. Identification of robust predictors of sustained treatment responses could be of high clinical importance. Methods: We used functional magnetic resonance imaging (fMRI; 3T General Electric) to assess 26 patients (85% women, mean age 32.3 years) with SAD. Blood-oxygen-level dependent (BOLD) responses to self-referential criticism, i.e. reading sentences such as “Nobody likes you” were compared to criticism referring to other individuals. Responses in the fear network, i.e. the amygdala, hippocampus, anterior cingulate cortex (ACC), and insula, were evaluated in a Support Vector Machine (SVM) approach to predict treatment outcome one-year after Internet-delivered CBT. We applied leave-one-out cross-validation to increase the generalizability of the data. Results: At one-year follow-up, three patients had dropped out. Twelve (52%) of the assessed patients met the response criteria, i.e. very much or much improved according to the Clinical Global Impression-Improvement scale (CGI-I). SVM on initial BOLD response, accurately classified patients according to responder status, based on multi-voxel patterns in the ACC (balanced accuracy of 91.7%, p=.001, Figure 1), and the ACC together with the amygdala (83.0%, p=.004) as well as the hippocampus (73.9%, p=.032). Conclusions: We demonstrate that initial multi-voxel BOLD response patterns to self-referential criticism in the ACC, amygdala, and hippocampus are highly predictive of long-term improvement of CBT in patients with SAD.

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