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Background: Noninvasive neurostimulation treatments are increasingly being used to treat major depression, which is a common cause of disability worldwide. While electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are both effective in treating depressive episodes, their mechanisms of action are, however, not completely understood. ECT is given under general anesthesia, where an electrical pulse is administered through electrodes placed on the patient's head to trigger a seizure. ECT is used for the most severe cases of depression and is usually not prescribed before other options have failed. With TMS, brain stimulation is achieved through rapidly changing magnetic fields that induce electric currents underneath a ferromagnetic coil. Its efficacy in depressive episodes has been well documented. This project aims to identify the neurobiological underpinnings of both the effects and side effects of the neurostimulation techniques ECT and TMS., Methods: The study will utilize a pre-post case control longitudinal design. The sample will consist of 150 subjects: 100 patients (bipolar and major depressive disorder) who are treated with either ECT (N = 50) or TMS (N = 50) and matched healthy controls (N = 50) not receiving any treatment. All participants will undergo multimodal magnetic resonance imaging (MRI) as well as neuropsychological and clinical assessments at multiple time points before, during and after treatment. Arterial spin labeling MRI at baseline will be used to test whether brain perfusion can predict outcomes. Signs of brain disruption, potentiation and rewiring will be explored with resting-state functional MRI, magnetic resonance spectroscopy and multishell diffusion weighted imaging (DWI). Clinical outcome will be measured by clinician assessed and patient reported outcome measures. Memory-related side effects will be investigated, and specific tests of spatial navigation to test hippocampal function will be administered both before and after treatment. Blood samples will be stored in a biobank for future analyses. The observation time is 6 months. Data will be explored in light of the recently proposed disrupt, potentiate and rewire (DPR) hypothesis., Discussion: The study will contribute data and novel analyses important for our understanding of neurostimulation as well as for the development of enhanced and more personalized treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT05135897., (© 2023. The Author(s).)

Background: Bipolar disorder (BD) is a chronic recurrent mood disorder associated with autonomic nervous system (ANS) dysfunction, indexed by heart rate variability (HRV). Changes in HRV between mood states are sparsely studied longitudinally. We aimed to compare HRV of hospitalized manic individuals with their own euthymic selves in a naturalistic observational study., Methods: 34 individuals were included, of which 16 were lost to follow-up. Ultimately 15 patients provided reliable heart rate data in both a manic and euthymic state, using photoplethysmography (PPG) sensor wristbands overnight. We calculated HRV measures Root Mean Square of Successive Differences (RMSSD), High-frequency (HF: 0.15-0.40 Hz), Low-frequency (LF: 0.40-0.15 Hz), Very low-frequency (VLF: 0.0033-0.04 Hz), Total power and Sample Entropy in 5-min night-time resting samples. We compared HRV measures by mood state within individuals using paired t -tests and linear regression to control for age and sex., Results: HRV was lower in the manic state when compared to the euthymic state for all HRV metrics ( p  ≤ 0.02), with large to medium effect sizes ( g  = 1.24 to 0.65). HRV changes were not significantly affected by age or sex., Conclusion: This longitudinal study provides evidence of lower HRV in manic states compared to euthymia, indicating an association between ANS dysregulation and changes in bipolar mood state. This corroborates previous cross-sectional studies, although the association may be less clear or reversed in hypomanic states. Further investigation in larger longitudinal samples is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stautland, Jakobsen, Fasmer, Osnes, Torresen, Nordgreen and Oedegaard.)

Background: Recurrent Major Depressive Disorder (MDD) is one of the most disabling mental disorders in modern society. Prior research has shown that self-compassion protects against ruminative tendencies, a key feature of recurrent MDD. In addition, self-compassion has been found to be positively related to higher psychophysiological flexibility (indexed by a higher vagally mediated heart rate variability; vmHRV) in young, healthy adults. To our knowledge, there is a lack of studies on how self-compassion relates to vmHRV in patients with recurrent MDD. The aim of the current study was to investigate whether higher self-compassion would associate with (1) lower ruminative tendencies and (2) higher vmHRV in a sample of adults with recurrent MDD., Methods: We included a sample of 63 patients (46 females) between 20 and 71 years old ( M = 40.24, SD = 12.8) with a history of three or more depressive episodes. They filled out the Self-Compassion Scale (SCS), Beck Depression Inventory (BDI), and Rumination Rating Scale (RRS). ECG (used to derive vmHRV) was acquired while resting and the square root of the mean squared differences of successive RR interval values (RMSSD) was calculated as measure of vmHRV., Results: As hypothesized, self-compassion was associated with lower ruminative tendencies. However, self-compassion was not associated with level of vmHRV. Several confounding variables were controlled for in the statistical analyses, and higher age predicted lower vmHRV across all statistical analyses., Conclusion: The results confirmed our hypothesis that higher self-compassion would be associated with lower ruminative tendencies in recurrent MDD. Contrary to our expectation, we did not find that the tendency to be more self-compassionate was associated with higher vmHRV. As such, higher self-compassion seems to relate with a lower tendency to ruminate about past mistakes and events but does not seem to relate to a flexible autonomic stress response (as indexed by higher vmHRV). Other potential explanatory factors for lower vmHRV in recurrent MDD is suggested as focus for exploration in future studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Svendsen, Schanche, Vøllestad, Visted, Jentschke, Karl, Binder, Osnes and Sørensen.)

Higher vagally mediated heart rate variability (vmHRV), reflecting vagal activity as indexed by heart function and lower stress vulnerability, is associated with higher perceived social support. Seeking social support is an adaptive stress response, and evolutionary theories suggest that females use this strategy more than males. The current study investigated the hypothesis that higher vmHRV is related to higher perceived social support under conditions of higher, relative to lower, stress, and that this association is most prominent in females. A healthy student sample ( n  = 143; 82 males, 61 females; mean age 19.9) completed the short version of the Medical outcomes study social support survey (MOS) and the Perceived stress scale (PSS). Activity in the high frequency band of heart rate variability (HF-HRV), deducted from five-minute resting electrocardiogram (ECG) recordings, indexed vmHRV. A moderation analysis was conducted, with PSS and sex as moderators of the association between vmHRV and MOS. Statistical effects were adjusted for age, education, physical activity, body mass index (BMI), alcohol and drug use, ECG-derived respiration (EDR), and mean heart rate. Higher PSS scores moderated the association between vmHRV and MOS in females but not males. Lower PSS scores did not moderate the relation between vmHRV and MOS. This suggests that higher vmHRV is associated with higher perceived social support under conditions of higher stress in females but not males, consistent with evolution of different stress management strategies in the sexes. The results may have implications for individualized intervention strategies for increasing vmHRV and perceived social support.

Introduction: Irritable bowel syndrome (IBS) is a common clinical label for medically unexplained gastrointestinal (GI) symptoms, recently described as a disturbance of the brain-gut-microbiota (BGM) axis. To gain a better understanding of the mechanisms underlying the poorly understood etiology of IBS, we have designed a multifaceted study that aim to stratify the complex interaction and dysfunction between the brain, the gut, and the microbiota in patients with IBS., Methods: Deep phenotyping data from patients with IBS (n = 100) and healthy age- (between 18 and 65) and gender-matched controls (n = 40) will be collected between May 2019 and December 2021. Psychometric tests, questionnaires, human biological tissue/samples (blood, faeces, saliva, and GI biopsies from antrum, duodenum, and sigmoid colon), assessment of gastric accommodation and emptying using transabdominal ultrasound, vagal activity, and functional and structural magnetic resonance imaging (MRI) of the brain, are included in the investigation of each participant. A subgroup of 60 patients with IBS-D will be further included in a 12-week low FODMAP dietary intervention-study to determine short and long-term effects of diet on GI symptoms, microbiota composition and functions, molecular GI signatures, cognitive, emotional and social functions, and structural and functional brain signatures. Deep machine learning, prediction tools, and big data analyses will be used for multivariate analyses allowing disease stratification and diagnostic biomarker detection., Discussion: To our knowledge, this is the first study to employ unsupervised machine learning techniques and incorporate systems-based interactions between the central and the peripheral components of the brain-gut-microbiota axis at the levels of the multiomics, microbiota profiles, and brain connectome of a cohort of 100 patients with IBS and matched controls; study long-term safety and efficacy of the low-FODMAP diet on changes in nutritional status, gut microbiota composition, and metabolites; and to investigate changes in the brain and gut connectome after 12 weeks strict low-FODMAP-diet in patients with IBS. However, there are also limitations to the study. As a restrictive diet, the low-FODMAP diet carries risks of nutritional inadequacy and may foster disordered eating patterns. Strict FODMAP restriction induces a potentially unfavourable gut microbiota, although the health effects are unknown., Trial Registration Number: NCT04296552 (ClinicalTrials.gov).

Background: The aim of this randomized wait-list controlled trial was to explore the effects of Mindfulness-Based Cognitive Therapy (MBCT) on risk and protective factors for depressive relapse within the domains of cognition, emotion and self-relatedness., Methods: Sixty-eight individuals with recurrent depressive disorder were randomized to MBCT or a wait-list control condition (WLC)., Results: Completers of MBCT (N = 26) improved significantly on measures assessing risk and protective factors of recurrent depression compared to WLC (N = 30) on measures of rumination (d = 0.59, p = .015), emotion regulation (d = 0.50, p = .028), emotional reactivity to stress (d = 0.32, p = .048), self-compassion (d = 1.02, p < .001), mindfulness (d = 0.59, p = .010), and depression (d = 0.40, p = .018). In the Intention To Treat sample, findings were attenuated, but there were still significant results on measures of rumination, self-compassion and depression., Conclusions: Findings from the present trial contribute to evidence that MBCT can lead to reduction in risk factors of depressive relapse, and strengthening of factors known to be protective of depressive relapse. The largest changes were found in the domain of self-relatedness, in the form of large effects on the participants' ability to be less self-judgmental and more self-compassionate., Trial Registration: ISRCTN, ISRCTN18001392. Registered 29 June 2018.

Objective: To investigate the relation between cardiac vagal activity (CVA), a measure of autonomic nervous system (ANS) flexibility, and self-reported emotion regulation (ER) difficulties in adolescents with attention-deficit/hyperactivity disorder (ADHD) and controls., Methods: The sample comprised 11-17-year-old adolescents with ADHD ( n =34) and controls ( n = 33). Multiple linear regression analyses investigated the relation between CVA, as indexed by high frequency heart rate variability (HF-HRV), and ER difficulties as assessed by the Difficulties in Emotion Regulation Scale (DERS). Supplemental analyses were performed in ADHD and control groups separately. Analyses assessed effects of body mass index (BMI), physical activity levels, and HF peak as a surrogate of respiration on CVA., Results: Lower CVA was associated with ER difficulties, and specifically with limited access to effective ER strategies. When investigating the relation between CVA and ER in the ADHD and control groups separately, there was a tendency of lower CVA predicting limited access to effective ER strategies in the ADHD group, and not in the control group., Conclusion: The results suggest that lower CVA, i.e., reduced ANS flexibility, in adolescents with ADHD and controls is associated with self-reported ER difficulties, and specifically with limited access to effective ER strategies. There was a tendency for lower CVA to predict limited ER strategies only in the adolescents with ADHD and not controls., (Copyright © 2020 Kvadsheim, Fasmer, Osnes, Koenig, Adolfsdottir, Eichele, Plessen and Sørensen.)

Background: Dispositional mindfulness and self-compassion are shown to associate with less self-reported emotional distress. However, previous studies have indicated that dispositional self-compassion may be an even more important buffer against such distress than dispositional mindfulness. To our knowledge, no study has yet disentangled the relationship between dispositional self-compassion and mindfulness and level of psychophysiological flexibility as measured with vagally mediated heart rate variability (vmHRV). The aim was thus to provide a first exploratory effort to expand previous research relying on self-report measures by including a psychophysiological measure indicative of emotional stress reactivity., Methods: Fifty-three university students filled out the "Five Facet Mindfulness Questionnaire" (FFMQ) and the "Self-Compassion Scale" (SCS), and their heart rate was measured during a 5 min resting electrocardiogram. Linear hierarchical regression analyses were conducted to examine the common and unique variance explained by the total scores of the FFMQ and the SCS on level of resting vmHRV., Results: Higher SCS total scores associated significantly with higher levels of vmHRV also when controlling for the FFMQ total scores. The SCS uniquely explained 7% of the vmHRV. The FFMQ total scores did not associate with level of vmHRV., Conclusion: These results offer preliminary support that dispositional self-compassion associates with better psychophysiological regulation of emotional arousal above and beyond mindfulness., (Copyright © 2020 Svendsen, Schanche, Osnes, Vøllestad, Visted, Dundas, Nordby, Binder and Sørensen.)

Juvenile onset of Major Depressive Disorder (MDD) is associated with increased likelihood of recurrent episodes of depression and more detrimental clinical trajectories. The aim of the current study was to investigate the effect of juvenile onset of MDD on emotion regulation as measured by self-report and Heart Rate Variability (HRV). Furthermore, we wanted to assess whether juvenile onset impacted the association between rumination and depressive symptoms. Sixty-four individuals with at least three prior episodes of MDD were recruited and filled out self-report questionnaires measuring rumination and emotion regulation abilities. In addition, electrocardiographic assessments were used to calculate HRV. Based on self-reported age of MDD onset, individuals were divided in two groups: Juvenile onset of MDD (first MDD episode before the age of 18, n = 30) and adult onset of MDD (first MDD episode after the age of 18, n = 34). Results showed that individuals whose first depressive episode occurred in childhood and adolescence reported more rumination and less emotional clarity compared to individuals who had their first episode of MDD in adulthood. Moreover, the tendency to ruminate was strongly associated with depressive symptoms in the juvenile onset of MDD group, whereas no such association was found in the adult onset group. There was no significant group difference for HRV. The findings are discussed in light of existing literature, in addition to suggesting how our findings may inform clinical practice and future research. We conclude that juvenile onset of MDD may lead to difficulties in emotion regulation and that these difficulties may increase depressive symptoms and vulnerability for relapse in this particular subgroup., (Copyright © 2019 Visted, Sørensen, Vøllestad, Osnes, Svendsen, Jentschke, Binder and Schanche.)

Background: A state of mindfulness refers to a present-centered attentional awareness without judging. Being mindful seems to increase the ability to be flexible and adaptive in attention focus according to situational contingencies. The way mindfulness affects such attentional control is often measured with three different but interacting attentional networks of alerting (preparedness), orienting (selection of stimulus), and conflict detection (suppression of irrelevant stimuli). In the current study, the aim was to study the effects of dispositional mindfulness on these attention networks, and specifically the effects on the interactions between these attention networks. Methods: Fifty participants between 19 and 29 years old filled out the questionnaire Five Facet Mindfulness Questionnaire (FFMQ) and performed the revised version of the Attention Network Test (ANT-R). The five FFMQ facets of Describing, Non-Judgment, Orienting, Non-Reactivity, and Acting with Awareness were included as predictors in multiple linear regression analyses with the ANT-R scores of alerting, orienting, conflict detection, and the interaction scores of alerting by conflict detection and orienting by conflict detection as outcome variables, respectively. Results: Higher dispositional mindfulness as measured with the five FFMQ facets predicted interaction scores (faster reaction times) of orienting by conflict detection, but none of the other ANT-R scores. It was specifically the FFMQ facets of Describing and non-judgment that predicted this lower interaction score of orienting by conflict detection. Conclusion: Our findings indicate that being mindful is associated with a more flexible and efficient orienting attention. It is associated with a higher ability to disengage from salient stimuli that is irrelevant to pursue goal-directed behavior (conflict detection).

Music can trigger emotional responses in a more direct way than any other stimulus. In particular, music-evoked pleasure involves brain networks that are part of the reward system. Furthermore, rhythmic music stimulates the basal ganglia and may trigger involuntary movements to the beat. In the present study, we created a continuously playing rhythmic, dance floor-like composition where the ambient noise from the MR scanner was incorporated as an additional instrument of rhythm. By treating this continuous stimulation paradigm as a variant of resting-state, the data was analyzed with stochastic dynamic causal modeling (sDCM), which was used for exploring functional dependencies and interactions between core areas of auditory perception, rhythm processing, and reward processing. The sDCM model was a fully connected model with the following areas: auditory cortex, putamen/pallidum, and ventral striatum/nucleus accumbens of both hemispheres. The resulting estimated parameters were compared to ordinary resting-state data, without an additional continuous stimulation. Besides reduced connectivity within the basal ganglia, the results indicated a reduced functional connectivity of the reward system, namely the right ventral striatum/nucleus accumbens from and to the basal ganglia and auditory network while listening to rhythmic music. In addition, the right ventral striatum/nucleus accumbens demonstrated also a change in its hemodynamic parameter, reflecting an increased level of activation. These converging results may indicate that the dopaminergic reward system reduces its functional connectivity and relinquishing its constraints on other areas when we listen to rhythmic music.

Difficulties in emotion regulation are associated with development and maintenance of psychopathology. Typically, features of emotion regulation are assessed with self-report questionnaires. Heart rate variability (HRV) is an objective measure proposed as an index of emotional regulation capacity. A limited number of studies have shown that self-reported difficulties in emotion regulation are associated with HRV. However, results from prior studies are inconclusive, and an ecological validation of the association has not yet been tested. Therefore, further exploration of the relation between self-report questionnaires and psychophysiological measures of emotional regulation is needed. The present study investigated the contribution of self-reported emotion regulation difficulties on HRV in a student sample. We expected higher scores on emotion regulation difficulties to be associated with lower vagus-mediated HRV (vmHRV). Sixty-three participants filled out the Difficulties in Emotion Regulation Scale and their resting HRV was assessed. In addition, a subsample of participants provided ambulatory 24-h HRV data, in order to ecologically validate the resting data. Correlation analyses indicated that self-reported difficulties in emotion regulation was negatively associated with vmHRV in both resting HRV and 24-h HRV. Specifically, when exploring the contribution of the different facets of emotion dysregulation, the inability to accept negative emotions showed the strongest association with HRV. The results are discussed and need for future research is described.

To what degree resting state fMRI is stable or susceptible to internal mind states of the individual is currently an issue of debate. To address this issue, the present study focuses on sex differences and investigates whether resting state fMRI is stable in men and women or changes within relative short-term periods (i.e., across the menstrual cycle). Due to the fact that we recently reported menstrual cycle effects on cognitive control based on data collected during the same sessions, the current study is particularly interested in fronto-parietal resting state networks. Resting state fMRI was measured in sixteen women during three different cycle phases (menstrual, follicular, and luteal). Fifteen men underwent three sessions in corresponding time intervals. We used independent component analysis to identify four fronto-parietal networks. The results showed sex differences in two of these networks with women exhibiting higher functional connectivity in general, including the prefrontal cortex. Menstrual cycle effects on resting states were non-existent. It is concluded that sex differences in resting state fMRI might reflect sexual dimorphisms in the brain rather than transitory activating effects of sex hormones on the functional connectivity in the resting brain.

Contrary to the classical view, recent neuroimaging studies claim that phonological processing, as part of auditory speech perception, is subserved by both the left and right temporal lobes and not the left temporal lobe alone. This study seeks to explore whether there are variations in the lateralization of response to verbal and nonverbal sounds by varying spectral complexity of those sounds. White noise was gradually transformed into either speech or music sounds using a "sound morphing" procedure. The stimuli were presented in an event-related design and the evoked brain responses were measured using fMRI. The results demonstrated that the left temporal lobe was predominantly sensitive to gradual manipulation of the speech sounds while the right temporal lobe responded to all sounds and manipulations. This effect was especially pronounced within the middle region of the left superior temporal sulcus (mid-STS). This area could be further subdivided into a more posterior area, which showed a linear response to the manipulation of speech sounds, and an anteriorly adjacent area which showed the strongest interaction between the speech and music sound manipulations. Such a differential and selective response was not seen in other brain areas and not when the sound "morphed" into a music stimulus. This gives further experimental evidence for the assumption of a posterior-anterior processing stream in the left temporal lobe. In addition, the present findings support the notion that the left mid STS area is more sensitive to speech signals compared to the right homologue.