Role of brain imaging in disorders of brain-gut interaction: a Rome Working Team Report.

Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required

Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study.

IntroductionChildhood maltreatment, a well-known risk factor for the development of substance abuse disorders, is associated with functional and structural abnormalities in the adult brain, particularly in the limbic system. However, almost no research has examined the relationship between childhood maltreatment and brain function in individuals with drug abuse disorders.MethodsWe conducted a pilot study of the relationship between childhood maltreatment (evaluated with the Childhood Trauma Questionnaire; Bernstein and Fink 1998) and resting-state functional connectivity of the amygdala (bilateral region of interest) with functional magnetic resonance imaging in 15 abstinent, methamphetamine-dependent research participants. Within regions that showed connectivity with the amygdala as a function of maltreatment, we also evaluated whether amygdala connectivity was associated positively with negative affect and negatively with healthy emotional processing.ResultsThe results indicated that childhood maltreatment was positively associated with resting-state connectivity between the amygdala and right hippocampus, right parahippocampal gyrus, right inferior temporal gyrus, right orbitofrontal cortex, cerebellum, and brainstem. Furthermore, connectivity between the amygdala and hippocampus was positively related to measures of depression, trait anxiety, and emotion dysregulation, and negatively related to self-compassion and dispositional mindfulness.ConclusionsThese findings suggest that childhood maltreatment may contribute to increased limbic connectivity and maladaptive emotional processing in methamphetamine-dependent adults, and that healthy emotion regulation strategies may serve as a therapeutic target to ameliorate the associated behavioral phenotype. Childhood maltreatment warrants further investigation as a potentially important etiological factor in the neurobiology and treatment of substance use disorders

The neural basis of unwanted thoughts during resting state.

Human beings are constantly engaged in thought. Sometimes thoughts occur repetitively and can become distressing. Up to now the neural bases of these intrusive or unwanted thoughts is largely unexplored. To study the neural correlates of unwanted thoughts, we acquired resting-state fMRI data of 41 female healthy subjects and assessed the self-reported amount of unwanted thoughts during measurement. We analyzed local connectivity by means of regional homogeneity (ReHo) and functional connectivity of a seed region. More unwanted thoughts (state) were associated with lower ReHo in right dorsolateral prefrontal cortex (DLPFC) and higher ReHo in left striatum (putamen). Additional seed-based analysis revealed higher functional connectivity of the left striatum with left inferior frontal gyrus (IFG) in participants reporting more unwanted thoughts. The state-dependent higher connectivty in left striatum was positively correlated with rumination assessed with a dedicated questionnaire focussing on trait aspects. Unwanted thoughts are associated with activity in the fronto-striatal brain circuitry. The reduction of local connectivity in DLPFC could reflect deficiencies in thought suppression processes, whereas the hightened activity in left striatum could imply an imbalance of gating mechanisms housed in basal ganglia. Its functional connectivity to left IFG is discussed as the result of thought-related speech processes

Stress-induced alterations in resting-state functional connectivity among adolescents with non-suicidal self-injury.

BACKGROUND Non-suicidal self-injury (NSSI) is a major mental health problem among youth worldwide. Dysfunction in emotion regulation contributes to NSSI, but research on the underlying neurobiological mechanisms of NSSI is limited. Adolescents with emotion regulation difficulties are vulnerable to stress, making them susceptible to maladaptive coping mechanisms such as NSSI. METHODS This study examined the functional neurocircuitry relevant to emotion regulation and stress coping in individuals with NSSI compared with healthy controls. This case-control study included 34 adolescents with NSSI (15.91 years) and 28 (16.0 years) unaffected controls. Participants underwent a functional magnetic resonance imaging scan before and after completing a laboratory stress-induction paradigm (the Montreal Imaging Stress Test). The effects of stress induction were quantified by both physiological measures and self-reports. RESULTS Participants with NSSI showed distinctive alterations in functional resting-state following stress induction, which differentiated them from unaffected controls. Results show a reduction in functional connectivity between frontoparietal regions and the angular gyrus within the patient group compared to controls, as well as an increase in functional connectivity between visual regions, the insular cortex, the planum polare, and the central opercular cortex. After conditions of acute stress, adolescents with NSSI show changes in functional connectivity of regions associated with sensorimotor alertness, attention, and effortful emotion regulation. LIMITATIONS The patient group showed both NSSI and suicidal behavior, therefore results might be partly due to suicidality. CONCLUSION The findings emphasize the importance of targeting emotion regulation within therapeutic approaches to enhance stress coping capacity, which in turn may contribute to counteracting self-injurious behavior

Psychobiological factors of resilience and depression in late life.

In contrast to traditional perspectives of resilience as a stable, trait-like characteristic, resilience is now recognized as a multidimentional, dynamic capacity influenced by life-long interactions between internal and environmental resources. We review psychosocial and neurobiological factors associated with resilience to late-life depression (LLD). Recent research has identified both psychosocial characteristics associated with elevated LLD risk (e.g., insecure attachment, neuroticism) and psychosocial processes that may be useful intervention targets (e.g., self-efficacy, sense of purpose, coping behaviors, social support). Psychobiological factors include a variety of endocrine, genetic, inflammatory, metabolic, neural, and cardiovascular processes that bidirectionally interact to affect risk for LLD onset and course of illness. Several resilience-enhancing intervention modalities show promise for the prevention and treatment of LLD, including cognitive/psychological or mind-body (positive psychology; psychotherapy; heart rate variability biofeedback; meditation), movement-based (aerobic exercise; yoga; tai chi), and biological approaches (pharmacotherapy, electroconvulsive therapy). Additional research is needed to further elucidate psychosocial and biological factors that affect risk and course of LLD. In addition, research to identify psychobiological factors predicting differential treatment response to various interventions will be essential to the development of more individualized and effective approaches to the prevention and treatment of LLD

Aberrant brain activation and coupling in Depression – Links between Psychopathology and Neurophysiology

Major Depressive Disorder (MDD) is the most common mental disorder and ranging under the top three of the most disabling diseases worldwide. Although various treatments exist for MDD, about 30 to 40 % of the patients don’t respond. A better understanding of the neurobiological correlates of MDD might lead to the development of new and the improvement of existing treatments. The dissertation at hand is dedicated to the aim of a better understanding of aberrant brain functioning and coupling in MDD. Further, we sought to investigate the behavioral and cognitive-affective underpinnings that lead to aberrant brain functioning and coupling in MDD, in terms of depressive rumination. In total this work comprises four studies. In our first study, we investigated the functional connectivity (FC) during resting state (rsFC) and task performance of the Trail Making Test (TMT) in subjects with late-life depression (LLD) and healthy controls (HC). FC was assessed via functional near-infrared spectroscopy (fNIRS) in areas of the cognitive control network (CCN). While we observed an expected pattern of change in FC in the healthy controls with relatively low FC during resting-state and an increase during task-performance, subjects with LLD showed an opposite pattern, with relatively high FC during resting-state and decreases during task-performance. Further, depressed and non-depressed subjects differed significantly during resting-state (LLD>HC) and the executive demanding condition of the TMT (HC>LLD). While these results were interesting from a standpoint of pathophysiological changes in FC, we couldn’t give a final explanation for the observed FC patterns in LLD. As a possible explanation, we assumed that some kind of depressive cognitive process could lead to hyper-connectivity within the CCN during resting-state that further disturbs cortical coupling during task performance. As depressive rumination is such a cognitive process that is common in depression, we developed a resting-state questionnaire to assess state rumination for subsequent studies. In study two, we investigated rsFC within subjects with MDD and HC with a parietal probeset covering parts of the default mode network (DMN), CCN and dorsal attention network (DAN). Further, we investigated in how far state- and trait rumination explained the differences between depressed and non-depressed subjects in rsFC. In contrast to our first study, we observed an opposite pattern of FC differences between the groups: within the parietal cortex, depressed subjects showed reduced FC in comparison to HC in a widespread bilateral network. While state rumination showed rather restricted effects, the measures of trait rumination showed wide-spread effects. Further, FC was negatively correlated with state- and trait rumination. Since our results so far were restricted to non-experimental between-subject associations, that don’t allow the investigation of causal relationships, we further designed a study in which we sought to induce rumination with the Trier Social Stress Test (TSST). In study three, we investigated the hemodynamic changes during the TSST in high and low trait ruminators in the CCN, further, we examined in how far state rumination would be induced through the TSST. Relationships between hemodynamic responses and state rumination were examined with a mediation analysis. As expected, we found increases in state rumination through the TSST. Further, these increases were higher in the high-trait ruminators. On a cortical level, low ruminators showed higher cortical activation in the stress condition than the high ruminators in the right inferior frontal gyrus (IFG). Further, group differences in post-stress state rumination were mediated by the cortical reactivity in this region. Subject with high IFG reactivity showed less state-rumination following the TSST. In study four, we further investigated in the same study cohort, if rsFC before and after stress would show an expected pattern with higher baseline FC in the high trait ruminators and a higher reactivity in rsFC in subjects with high increases in state rumination. As expected, baseline levels of rsFC were increased in the high-ruminators like in our first study for the LDD group. However, although state rumination increased in the high trait ruminators more strongly than in the low trait ruminators, rsFC only increased in the latter group. Since we didn’t observe a co-variation of change scores between rsFC and state rumination, we concluded that the effect of rumination on FC changes would be an indirect one. In the general discussion of this dissertation, I propose a model of indirect prolonged stress effects in high ruminating subjects that lead to higher stress levels and subsequently to permanent changes in FC. This model would explain the observed effects in our study and is in line with current research of FC alterations in chronic stress. I further outline, in how far the presented results and the research of biological underpinnings could improve the current theory development of mental diseases as well as treatment planning

Coping with brief periods of food restriction: mindfulness matters

The obesity epidemic had spawned considerable interest in understanding peoples' responses to palatable food cues that are plentiful in obesogenic environments. In this paper we examine how trait mindfulness of older, obese adults may moderate brain networks that arise from exposure to such cues. Nineteen older, obese adults came to our laboratory on two different occasions. Both times they ate a controlled breakfast meal and then were restricted from eating for 2.5 h. After this brief period of food restriction, they had an fMRI scan in which they were exposed to food cues and then underwent a 5 min recovery period to evaluate brain networks at rest. On one day they consumed a BOOST® liquid meal prior to scanning, whereas on the other day they only consumed water (NO BOOST® condition). We found that adults high in trait mindfulness were able to return to their default mode network (DMN), as indicated by greater global efficiency in the precuneus, during the post-exposure rest period. This effect was stronger for the BOOST® than NO BOOST® treatment condition. Older adults low in trait mindfulness did not exhibit this pattern in the DMN. In fact, the brain networks of those low on the MAAS suggests that they continued to be pre-occupied with the elaboration of food cues even after cue exposure had ended. Further work is needed to examine whether mindfulness-based therapies alter brain networks to food cues and whether these changes are related to eating behavior

Preliminary Evidence That CD38 Moderates the Association of Neuroticism on Amygdala-Subgenual Cingulate Connectivity.

CD38 genetic variation has been associated with autism spectrum disorders and social anxiety disorder, which may result from CD38's regulation of oxytocin secretion. Converging evidence has found that the rs3796863 A-allele contributes to increased social sensitivity compared to the CC genotype. The current study examined the moderating role of CD38 genetic variants (rs3796863 and rs6449182) that have been associated with enhanced (or reduced) social sensitivity on neural activation related to neuroticism, which is commonly elevated in individuals with social anxiety and depression. Adults (n = 72) with varying levels of social anxiety and depression provided biological samples for DNA extraction, completed a measure of neuroticism, and participated in a standardized emotion processing task (affect matching) while undergoing fMRI. A significant interaction effect was found for rs3796863 x neuroticism that predicted right amygdala-subgenual anterior cingulate cortex (sgACC) functional connectivity. Simple slopes analyses showed a positive association between neuroticism and right amygdala-sgACC connectivity among rs3796863 A-allele carriers. Findings suggest that the more socially sensitive rs3796863 A-allele may partially explain the relationship between a known risk factor (i.e. neuroticism) and promising biomarker (i.e. amygdala-sgACC connectivity) in the development and maintenance of social anxiety and depression