Where alcohol use disorder meets interoception: A meta-analytic view on structural and functional neuroimaging data.

Alcohol use disorder (AUD) has been associated with changes in the processing of internal body signals, known as interoception. Changes in brain structure, particularly in the insula, are thought to underlie impaired interoception. As studies specifically investigating this association are largely lacking, this analysis takes an approach that compares meta-analytic results on interoception with recently published meta-analytic results on gray matter reduction in AUD. A systematic literature search identified 25 eligible interoception studies. Activation likelihood estimation (ALE) was used to test for spatial convergence of study results. Overlap between interoception and AUD clusters was tested using conjunction analysis. Meta-analytic connectivity modeling (MACM) and resting-state functional connectivity were used to identify the functional network of interoception and to test where this network overlapped with AUD meta-analytic clusters. The results were characterized using behavioral domain analysis. The interoception ALE identified a cluster in the left middle insula. There was no overlap with clusters of reduced gray matter in AUD. MACM analysis of the interoception cluster revealed a large network located in the insulae, thalami, basal nuclei, cingulate and medial frontal cortices, and pre- and postcentral gyri. Resting state analysis confirmed this result, showing the strongest connections to nodes of the salience- and somatomotor network. Five of the eight clusters that showed a structural reduction in AUD were located within these networks. The behavioral profiles of these clusters were suggestive of higher-level processes such as salience control, somatomotor functions, and skin sensations. The results suggest an altered salience mapping of interoceptive signals in AUD, consistent with current models. Connections to the somatomotor network may be related to action control and integration of skin sensations. Mindfulness-based interventions, pleasurable touch, and (deep) transcranial magnetic stimulation may be targeted interventions that reduce interoceptive deficits in AUD and thus contribute to drug use reduction and relapse prevention.

HPA axis stress reactivity and hair cortisol concentrations in recently detoxified alcoholics and healthy controls with and without childhood maltreatment.

Childhood maltreatment (CM) is a strong risk factor for alcohol dependence (AD) and is associated with a more severe course of the disease. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis may play an important role in this relationship. The aim of the present study was to systematically investigate potential alterations in HPA functioning associated with AD diagnosis and CM. Four study groups were recruited: AD patients with (n = 29; 10♀) and without (n = 33; 8♀) CM and healthy controls with (n = 30; 20♀) and without (n = 38; 15♀) CM. Cumulative cortisol secretion was measured by hair cortisol concentration (HCC). To measure HPA axis response to the Trier social stress test (TSST), saliva and blood samples were analysed for adrenocorticotropic hormone (ACTH) and cortisol. In the AD groups, the period of hair growth covered acute alcohol consumption and withdrawal. The TSST was scheduled after completion of withdrawal. Irrespective of CM, higher HCCs and reduced ACTH and cortisol levels before and after TSST were observed in AD patients. The analyses did not reveal any differences between AD patients with and without CM. Healthy controls with CM had lower plasma cortisol levels compared with those without CM. The results suggest that AD is strongly related to HPA axis functioning, which may superimpose possible differences between AD patients with and without CM. Future studies should investigate whether biologically different subtypes of AD with and without CM can be identified in earlier stages or before the development of AD.

Does prior traumatization affect the treatment outcome of CBT for panic disorder? The potential role of the MAOA gene and depression symptoms.

Although cognitive behavioral therapy (CBT) is highly effective in the treatment of anxiety disorders, many patients still do not benefit. This study investigates whether a history of traumatic event experience is negatively associated with outcomes of CBT for panic disorder. The moderating role of the monoamine oxidase A (MAOA) gene and depression symptoms as well as the association between trauma history and fear reactivity as a potential mechanism are further analyzed. We conducted a post-hoc analysis of 172 male and 60 female patients with panic disorder treated with CBT in a multi-center study. Treatment outcome was assessed at post-treatment using self-report and clinician rating scales. Fear reactivity before treatment was assessed via heart rate and self-reported anxiety during a behavioral avoidance test. Among females, we did not find any differences in treatment response between traumatized and non-traumatized individuals or any two-way interaction trauma history × MAOA genotype. There was a significant three-way interaction trauma history × MAOA genotype × depression symptoms on all treatment outcomes indicating that in traumatized female patients carrying the low-activity allele, treatment effect sizes decreased with increasing depression symptoms at baseline. No such effects were observed for males. In conclusion, we found no evidence for a differential treatment response in traumatized and non-traumatized individuals. There is preliminary evidence for poorer treatment outcomes in a subgroup of female traumatized individuals carrying the low-active variant of the MAOA gene. These patients also report more symptoms of depression symptomatology and exhibit a dampened fear response before treatment which warrants further investigation.

Biological stress indicators as risk markers for increased alcohol use following traumatic experiences.

Alcohol misuse is a common sequela of traumatic event experiences causing considerable morbidity and mortality. Although biological stress indicators have been identified as useful risk markers for the development of trauma-related disorders, no such biological indicators exist for the risk of increased alcohol use after trauma exposure. This is the first study to prospectively investigate the predictive value of long-term cortisol levels and acute stress reactivity for the risk of increased alcohol use following traumatic events. Male soldiers were examined before and 12 months following deployment using a standardized diagnostic interview. We analyzed the moderating role of baseline hair cortisol concentrations (HCCs, n = 153) as well as baseline salivary cortisol and alpha-amylase stress reactivity in response to a laboratory stressor (n = 145) in the association between new-onset traumatic events (according to the DSM-IV A1 criterion) and subsequent daily alcohol use. No main effects of pre-traumatic HCC or salivary stress markers on subsequent change in alcohol use were observed. However, we found that with decreasing HCC, the number of new-onset traumatic events was more strongly associated with subsequent alcohol use independent from changes in posttraumatic stress disorder symptoms. No such relation was seen for the acute stress reactivity data. Taken together, this study provides first evidence suggesting that individual differences in long-term cortisol regulation are involved in the association between traumatic experiences and subsequent alcohol use. HCC may thus serve as a potential target in the early identification of individuals vulnerable for increased alcohol use following traumatic events.

Epigenetic variation in the serotonin transporter gene predicts resting state functional connectivity strength within the salience-network.

Genetic variation in the serotonin transporter gene (SLC6A4) has been associated with psychopathology and aberrant brain functioning in a plethora of clinical and imaging studies. In contrast, the neurobiological correlates of epigenetic signatures in SLC6A4, such as DNA methylation profiles, have only recently been explored in human brain imaging research. The present study is the first to apply a resting state functional magnetic resonance imaging approach to identify changes in brain networks related to SLC6A4 promoter methylation (N=74 healthy individuals). The amygdalae were defined as seed regions given that resting state functional connectivity in this brain area is under serotonergic control and relates to a broad range of psychiatric phenotypes. We further used bisulfite pyrosequencing to analyze quantitative methylation at 83 CpG sites within a promoter-associated CpG island of SLC6A4 from blood-derived DNA samples. The major finding of this study indicates a positive relation of SLC6A4 promoter methylation and amygdaloid resting state functional coupling with key nodes of the salience network (SN) including the anterior insulae and the dorsal anterior cingulate cortices. Increased intra-network connectivity in the SN is thought to facilitate the detection and subsequent processing of potentially negative stimuli and reflects a core feature of psychopathology. As such, epigenetic changes within the SLC6A4 gene predict connectivity patterns in clinically and behaviorally relevant brain networks which may in turn convey increased disease susceptibility.

Substance use disorders are characterised by increased voxel-wise intrinsic measures in sensorimotor cortices: An ALE meta-analysis.

Substance use disorders (SUDs) are severe psychiatric illnesses. Seed region and independent component analyses are currently the dominant connectivity measures but carry the risk of false negatives due to selection. They can be complemented by a data-driven and whole-brain usage of voxel-wise intrinsic measures (VIMs). We meta-analytically integrated VIMs, namely regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF), voxel-mirrored homotopy connectivity (VMHC) and degree centrality (DC) across different SUDs using the Activation Likelihood Estimation (ALE) algorithm, functionally decoded emerging clusters, and analysed their connectivity profiles. Our systematic search identified 51 studies including 1439 SUD participants. Although no overall convergent pattern of alterations across VIMs in SUDs was found, sensitivity analyses demonstrated two ALE-derived clusters of increased ReHo and ALFF in SUDs, which peaked in the left pre- and postcentral cortices. Subsequent analyses showed their involvement in action execution, somesthesis, finger tapping and vibrotactile monitoring/discrimination. Their numerous clinical correlates across included studies highlight the under-discussed role of sensorimotor cortices in SUD, urging a more attentive exploration of their clinical significance.

Neural underpinnings of response inhibition in substance use disorders: weak meta-analytic evidence for a widely used construct.

RATIONALE: Substance use disorders (SUDs) rank among the most severely debilitating psychiatric conditions. Among others, decreased response inhibition capacities could make it more difficult for patients to abstain from drug use and maintain abstinence. However, meta-analyses on the neural basis of response inhibition in SUDs yielded conflicting results. OBJECTIVE: In this study, we revisited the neuroimaging research field and summarized the existing fMRI literature on overt response inhibition (Go/NoGo and stop-signal paradigms) across different SUDs. METHODS: We performed a systematic literature review and an activation likelihood estimation (ALE) meta-analysis to investigate the actual convergence of functional deviations observed in SUD samples. Results were further supplied by consecutive robustness measures and a post-hoc random-effects meta-analysis of behavioural data. RESULTS: We identified k = 21 eligible studies for our analysis. The ALE analysis indicated a significant cluster of convergence with its statistical peak in the right anterior insula. Consecutive analyses, however, indicated this result was not robust and susceptible towards publication bias. Additionally, a post-hoc random effects meta-analysis of the behavioural parameters of Go/NoGo and stop-signal paradigms reported by the included studies revealed no significant differences in task performance comparing SUD samples and controls. CONCLUSION: We discuss that the role of task-based response inhibition may require some refinement as an overarching marker for SUD pathology. Finally, we give a few prospects for future research that should be further explored in this context.

Flexible processing of distractor stimuli under stress.

Acute stress is assumed to affect executive processing of stimulus information, although extant studies have yielded heterogeneous findings. The temporal flanker task, in which a target stimulus is preceded by a distractor of varying utility, offers a means of investigating various components involved in the adjustment of information processing and conflict control. Both behavioral and EEG data obtained with this task suggest stronger distractor-related response activation in conditions associated with higher predictivity of the distractor for the upcoming target. In two experiments we investigated distractor-related processing and conflict control after inducing acute stress (Trier Social Stress Test). Although the stressed groups did not differ significantly from unstressed control groups concerning behavioral markers of attentional adjustment (i.e., Proportion Congruent Effect), or event-related sensory components in the EEG (i.e., posterior P1 and N1), the lateralized readiness potential demonstrated reduced activation evoked by (predictive) distractor information under stress. Our results suggest flexible adjustment of attention under stress but hint at decreased usage of nominally irrelevant stimulus information for biasing response selection.

The ad-libitum taste test as measure of momentary alcohol use in the laboratory: an investigation of construct validity and confounding factors.

RATIONALE: The ad-libitum taste test is a widely used covert measure of motivation to consume alcohol in the laboratory. However, studies on its construct validity and potential confounding factors are scarce. OBJECTIVES: This study aimed to evaluate the construct validity of the ad-libitum taste test by examining the association of ad-libitum alcohol consumption with typical alcohol use and craving, and investigating potential moderation by trait anxiety, depressiveness, current mood, and drinking motives. METHODS: A sample of 264 young male individuals were offered two 0.33 l glasses of beer. Participants were instructed to rate the characteristics of each drink, while the percentage of beverages containing alcohol consumed was assessed. Associations of ad-libitum consumption with typical alcohol use and craving were assessed using non-parametric and piecewise regressions. Moreover, moderator analysis with trait anxiety, depressiveness, current mood, and drinking motives was carried out. RESULTS: Ad-libitum alcohol consumption was associated with typical alcohol use and alcohol craving. However, these associations decreased at high consumption levels. Associations between ad-libitum consumption, typical alcohol use, and craving were stable across several conditions, except that the association between ad-libitum consumption and craving increased with higher social, conformity, and coping drinking motives. CONCLUSIONS: The ad-libitum taste test appears to be a valid measure of the motivation to drink alcohol in laboratory studies in young male adults, although this validity might be compromised at high levels of ad-libitum consumption. Consideration of these factors can contribute to further refining the ad-libitum taste test as a valuable tool for assessing motivation to consume alcohol in laboratory studies.

Cortical and Subcortical Brain Alterations in Specific Phobia and Its Animal and Blood-Injection-Injury Subtypes: A Mega-Analysis From the ENIGMA Anxiety Working Group.

OBJECTIVE: Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults). METHODS: Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis. RESULTS: Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents. CONCLUSIONS: Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.

High and low worriers do not differ in unstimulated resting-state brain connectivity.

Chronic, excessive and uncontrollable worry presents an anxiety rising and distressing mental activity relevant in a range of psychological disorders. Task based studies investigating its underlying neural mechanisms reveal fairly heterogenous results. The current study aimed to investigate pathological worry related effects on the functional neural network architecture in the resting unstimulated brain. Using resting-state functional magnetic resonance imaging (rsfMRI) we compared functional connectivity (FC) patterns between 21 high worriers and 21 low worriers. We, on the one hand, conducted a seed-to-voxel analysis based on recent meta-analytic findings and, on the other hand, implemented a data-driven multi voxel pattern analysis (MVPA) approach to yield brain clusters showing connectivity differences between the two groups. Additionally, the seed regions and MVPA were used to investigate whether whole brain connectivity is associated with momentary state worry across groups. The data did not reveal differences in resting-state FC related to pathological worry, neither by the seed-to-voxel or MVPA approach testing for differences linked to trait worry nor by using the MVPA to test for state worry related aberrations. We discuss whether the null findings in our analyses are related to spontaneous fluctuations in momentary worry and the associated presence of multiple fluctuating brain states that could cause mutually cancelling effects. For future studies investigating the neural correlates of excessive worry, we propose a direct worry induction for better control of the situation.

The association between repetitive negative thinking and distress across mental disorders: Preliminary findings from an outpatient treatment-seeking sample.

Distress is a characteristic of various mental disorders. The transdiagnostic construct repetitive negative thinking (RNT) has been suggested to contribute to distress. However, there is little evidence that this association can actually be found across diagnostic categories. We analyzed this association for phobias, other anxiety disorders, stress disorders, depressive disorders and substance use disorders in 194 treatment-seeking individuals. RNT was associated with distress across all diagnostic categories with high effect sizes. Except for phobias, these associations were not attributable to general emotion regulation abilities. RNT might contribute to distress in several mental disorders which underlines its potential for transdiagnostic interventions.

Underlying mechanisms in the relationship between stress and alcohol consumption in regular and risky drinkers (MESA): methods and design of a randomized laboratory study.

BACKGROUND: Excessive alcohol consumption and alcohol use disorders (AUD) are among the leading preventable causes of premature morbidity and mortality and are considered a major public health concern. In order to reduce the individual and societal burden of excessive alcohol use, it is crucial to identify high-risk individuals at earlier stages and to provide effective interventions to prevent further progression. Stressful experiences are important risk factors for excessive alcohol consumption and AUDs. However, the underlying biological and psychological mechanisms are still poorly understood. METHODS: The project "Underlying mechanisms in the relationship between stress and alcohol consumption in regular and risky drinkers (MESA)" is a randomized controlled study that started in December 2018 and is conducted in a laboratory setting, which aims to identify moderators and mediators of the relationship between acute stress and alcohol consumption among regular and risky drinkers. Regular and risky drinkers are randomly assigned to a stress induction or a control condition. Several processes that may mediate (emotional distress, endocrine and autonomic stress reactivity, impulsivity, inhibitory control, motivational sensitization) or moderate (trait impulsivity, childhood maltreatment, basal HPA-axis activity) the relation between stress and alcohol consumption are investigated. As primary dependent variable, the motivation to consume alcohol following psychosocial stress is measured. DISCUSSION: The results of this study could help to provide valuable targets for future research on tailored interventions to prevent stress-related alcohol consumption.

A coordinate-based meta-analysis of white matter alterations in patients with alcohol use disorder.

INTRODUCTION: Besides the commonly described gray matter (GM) deficits, there is growing evidence of significant white matter (WM) alterations in patients with alcohol use disorder (AUD). WM changes can be assessed using volumetric and diffusive magnetic resonance imaging methods, such as voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). The aim of the present meta-analysis is to investigate the spatial convergence of the reported findings on WM alterations in AUD. METHODS: Systematic literature search on PubMed and further databases revealed 18 studies eligible for inclusion, entailing a total of 462 AUD patients and 416 healthy controls (up to January 18, 2021). All studies that had used either VBM or DTI whole-brain analyzing methods and reported results as peak-coordinates in standard reference space were considered for inclusion. We excluded studies using approaches non-concordant with recent guidelines for neuroimaging meta-analyses and studies investigating patient groups with Korsakoff syndrome or other comorbid substance use disorders (except tobacco). RESULTS: Anatomical likelihood estimation (ALE) revealed four significant clusters of convergent macro- and microstructural WM alterations in AUD patients that were assigned to the genu and body of the corpus callosum, anterior and posterior cingulum, fornix, and the right posterior limb of the internal capsule. DISCUSSION: The changes in WM could to some extent explain the deteriorations in motor, cognitive, affective, and perceptual functions seen in AUD. Future studies are needed to clarify how WM alterations vary over the course of the disorder and to what extent they are reversible with prolonged abstinence.

How specific is specific phobia? Different neural response patterns in two subtypes of specific phobia.

Specific phobia of the animal subtype has been employed as a model disorder exploring the neurocircuitry of anxiety disorders, but evidence is lacking whether the detected neural response pattern accounts for all animal subtypes, nor across other phobia subtypes. The present study aimed at directly comparing two subtypes of specific phobia: snake phobia (SP) representing the animal, and dental phobia (DP) representing the blood-injection-injury subtype. Using functional magnetic resonance imaging (fMRI), brain activation and skin conductance was measured during phobogenic video stimulation in 12 DP, 12 SP, and 17 healthy controls. For SP, the previously described activation of fear circuitry structures encompassing the insula, anterior cingulate cortex and thalamus could be replicated and was furthermore associated with autonomic arousal. In contrast, DP showed circumscribed activation of the prefrontal and orbitofrontal cortex (PFC/OFC) when directly compared to SP, being dissociated from autonomic arousal. Results provide preliminary evidence for the idea that snake and dental phobia are characterized by distinct underlying neural systems during sustained emotional processing with evaluation processes in DP being controlled by orbitofrontal areas, whereas phobogenic reactions in SP are primarily guided by limbic and paralimbic structures. Findings support the current diagnostic classification conventions, separating distinct subtypes in DSM-IV-TR. They highlight that caution might be warranted though for generalizing findings derived from animal phobia to other phobic and anxiety disorders. If replicated, results could contribute to a better understanding of underlying neurobiological mechanisms of specific phobia and their respective classification.

Meta-analysis of grey matter changes and their behavioral characterization in patients with alcohol use disorder.

Alcohol Use Disorder (AUD) is associated with reductions in grey matter (GM) volume which can lead to changes in numerous brain functions. The results of previous studies on altered GM in AUD differ considerably in the regions identified. Three meta-analyses carried out between 2014 and 2017 yielded different results. The present study includes the considerable amount of newer research and delivers a state-of-the art meta-analysis in line with recently published guidelines. Additionally, we behaviorally characterized affected regions using fMRI metadata and identified related brain networks by determining their meta-analytic connectivity patterns. Twenty-seven studies with 1,045 AUD patients and 1,054 healthy controls were included in the analysis and analyzed by means of Anatomical Likelihood Estimation (ALE). GM alterations were identified in eight clusters covering different parts of the cingulate and medial frontal gyri, paracentral lobes, left post- and precentral gyri, left anterior and right posterior insulae and left superior frontal gyrus. The behavioral characterization associated these regions with specific cognitive, emotional, somatosensory and motor functions. Moreover, the clusters represent nodes within behaviorally relevant brain networks. Our results suggest that GM reduction in AUD could disrupt network communication responsible for the neurocognitive impairments associated with high chronic alcohol consumption.

Effects of acute psychosocial stress on working memory related brain activity in men.

Acute psychosocial stress in humans triggers the release of glucocorticoids (GCs) and influences performance in declarative and working memory (WM) tasks. These memory systems rely on the hippocampus and prefrontal cortex (PFC), where GC-binding receptors are present. Previous studies revealed contradictory results regarding effects of acute stress on WM-related brain activity. We combined functional magnetic resonance imaging with a standardized psychosocial stress protocol to investigate the effects of acute mental stress on brain activity during encoding, maintenance, and retrieval of WM. Participants (41 healthy young men) underwent either a stress or a control procedure before performing a WM task. Stress increased salivary cortisol levels and tended to increase WM accuracy. Neurally, stress-induced increases in cortical activity were evident in PFC and posterior parietal cortex (PPC) during WM maintenance. Furthermore, hippocampal activity was modulated by stress during encoding and retrieval with increases in the right anterior hippocampus during WM encoding and decreases in the left posterior hippocampus during retrieval. Our study demonstrates that stress increases activity in PFC and PPC specifically during maintenance of items in WM, whereas effects on hippocampal activity are restricted to encoding and retrieval. The finding that psychosocial stress can increase and decrease activity in two different hippocampal areas may be relevant for understanding the often-reported phase-dependent opposing behavioral effects of stress on long-term memory.

No association between FKBP5 gene methylation and acute and long-term cortisol output.

Prior studies identified DNA methylation (DNAM) changes in a regulatory region within the FK506 binding protein 5 (FKBP5) gene as a crucial mediator of long-term negative health outcomes following early adversity. A critical mechanism underlying this link, in turn, has been suggested to be epigenetically induced dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The purpose of this study was thus to investigate associations of FKBP5 DNAM with both acute and chronic cortisol output. Two hundred adults with differential exposure to childhood trauma (CT) were underwent a laboratory stressor (Trier Social Stress Test) and provided salivary samples for the analysis of acute cortisol stress responses. In addition, hair cortisol concentrations were determined as a valid measure of integrated long-term cortisol levels. Whole blood samples were drawn for DNAM analyses of FKBP5 intron 7 via bisulfite pyrosequencing. In contrast to most prior work, only healthy participants were included in order to disentangle the effects of trauma exposure per se from those related to mental disorders. First, our findings did not reveal strong evidence for a robust effect of CT on FKBP5 intron 7 DNAM status, even if genetic predisposition (rs1360780 genotype) was taken into account. Second, FKBP5 DNAM levels were found to be unrelated to acute cortisol stress reactivity and long-term cortisol concentration in hair. The failure to demonstrate a significant association between CT and FKBP5 DNAM in an exclusively healthy sample could be interpreted as suggesting that individuals' mental health status may be a critical modulator of previously observed effects.

FKBP5 methylation predicts functional network architecture of the rostral anterior cingulate cortex.

DNA methylation (DNAM) changes in the FKBP5 gene have been identified as a potential molecular mechanism explaining how environmental adversity may confer long-term health risks. However, the neurobiological correlates of epigenetic signatures in FKBP5 have only recently been explored in human brain imaging research. The present study aims to investigate associations of FKBP5 DNAM and functional network architecture during an implicit emotion regulation task (N = 74 healthy individuals). For this, we applied a data-driven multi-voxel pattern analysis (MVPA) to identify regions, where connectivity values vary as a function of FKBP5 DNAM, which then served as seed regions for functional network architecture analyses. Blood-derived DNA samples were obtained to analyze quantitative DNAM at three CpGs sites in intron 7 of the FKBP5 gene using bisulfite pyrosequencing. MPVA revealed a cluster within the right rostral ACC and the paracingulate ACCs, where connectivity patterns were strongly related to FKBP5 DNAM. Using this cluster as seed region for connectivity analyses, we further identified a functional network, including prefrontal, subcortical, insular, and thalamic regions, where connectivity patterns positively correlated with FKBP5 DNAM. A subsequent behavioral domain analyses to determine the functional specialization of this network revealed highest effect sizes for subdomains that represent affective and cognitive processes. Together, these findings suggest that FKBP5 demethylation predicts a widespread functional disruption in a brain network centrally implicated in emotion regulation and cognition, which may in turn convey increased disease susceptibility.

Cortisol secretion predicts functional macro-scale connectivity of the visual cortex: A data-driven Multivoxel Pattern Analysis (MVPA).

BACKGROUND: Functional connectivity is a fundamental principle of brain organization. Cortisol, the end product of the hypothalamic-pituitary-adrenal axis, is a potent modulator of brain functions. Previous studies investigating the association between cortisol levels on brain connectivity are, however, limited to specifica priori defined brain networks. Such hypothesis-driven approaches only partly capture the full extent of spatial modulatory effects that cortisol exerts on brain connectivity. Consequently, the aim of this study was a data-driven identification of brain regions where connectivity patterns covary significantly with cortisol levels. METHODS: Eighty-eight healthy right-handed individuals participated in a task-independent fMRI-resting-state functional connectivity (rsFC) measurement. The cortisol concentrations in saliva were measured at eight points in time around the resting state measurement. Using a multi-voxel pattern analysis (MVPA), seed regions were identified whose activity covaried strongest with cortisol levels. Seed-to-voxel analyses were then performed to isolate corresponding networks affected by cortisol variation. RESULTS: The MVPA identified three regions in the primary and secondary visual cortex where connectivity patterns were associated with cortisol secretion. Seed-to-voxel analysis revealed large lateral connectivity clusters that mainly correspond to the salience and control network, but also to auditory and pericentral regions. Subsequent dose-response analysis suggests that cortisol levels below ∼10 nmol/L weakly influenced connectivity between the identified regions. DISCUSSION: The results indicate a dose-dependent association between cortisol levels and the rsFC of the visual cortex to several lateral brain regions associated with perception, attention, cognition, salience mapping and motor actions. It is possible that the effects of cortisol on cognitive functions may be (at least partially) mediated by cortisol effects on the underlying sensory processes.