Association between resting-state connectivity patterns in the defensive system network and treatment response in spider phobia-a replication approach.

Although highly effective on average, exposure-based treatments do not work equally well for all patients with anxiety disorders. The identification of pre-treatment response-predicting patient characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to identify pre-treatment neural signatures differing between exposure treatment responders and non-responders in spider phobia and to validate results through rigorous replication. Data of a bi-centric intervention study comprised clinical phenotyping and pre-treatment resting-state functional connectivity (rsFC) data of n = 79 patients with spider phobia (discovery sample) and n = 69 patients (replication sample). RsFC data analyses were accomplished using the Matlab-based CONN-toolbox with harmonized analyses protocols at both sites. Treatment response was defined by a reduction of >30% symptom severity from pre- to post-treatment (Spider Phobia Questionnaire Score, primary outcome). Secondary outcome was defined by a reduction of >50% in a Behavioral Avoidance Test (BAT). Mean within-session fear reduction functioned as a process measure for exposure. Compared to non-responders and pre-treatment, results in the discovery sample seemed to indicate that responders exhibited stronger negative connectivity between frontal and limbic structures and were characterized by heightened connectivity between the amygdala and ventral visual pathway regions. Patients exhibiting high within-session fear reduction showed stronger excitatory connectivity within the prefrontal cortex than patients with low within-session fear reduction. Whereas these results could be replicated by another team using the same data (cross-team replication), cross-site replication of the discovery sample findings in the independent replication sample was unsuccessful. Results seem to support negative fronto-limbic connectivity as promising ingredient to enhance response rates in specific phobia but lack sufficient replication. Further research is needed to obtain a valid basis for clinical decision-making and the development of individually tailored treatment options. Notably, future studies should regularly include replication approaches in their protocols.

Mechanisms of action underlying virtual reality exposure treatment in spider phobia: Pivotal role of within-session fear reduction.

Although virtual-reality exposure treatment (VRET) for anxiety disorders is an efficient treatment option for specific phobia, mechanisms of action for immediate and sustained treatment response need to be elucidated. Towards this aim, core therapy process variables were assessed as predictors for short- and long-term VR treatment outcomes. In a bi-centric study, n = 186 patients with spider phobia completed a baseline-assessment, a one-session VRET, a post-therapy assessment, and a 6-month-follow-up assessment (ClinicalTrials.gov, ID: NCT03208400). Short- and long-term outcomes regarding self-reported symptoms in the spider phobia questionnaire (SPQ) and final patient-spider distance in the behavioral avoidance test (BAT) were predicted via logistic regression models with the corresponding baseline score, age, initial fear activation, within-session fear reduction and fear expectancy violation as predictors. To predict long-term remission status at 6-month-follow-up, dimensional short-term changes in the SPQ and BAT were additionally included. Higher within-session fear reductions predicted better treatment outcomes (long-term SPQ; short- and long-term BAT). Lower initial fear activation tended to be associated with better long-term outcomes (SPQ), while fear expectancy violation was not associated with any outcome measure. Short-term change in the SPQ predicted remission status. Findings highlight that in VRET for spider phobia, the experience of fear reduction is central for short- and long-term treatment success and should be focused by therapists.

Emotion processing in depression with and without comorbid anxiety disorder.

BACKGROUND: Among mental disorders, major depressive disorder (MDD) is highly prevalent and associated with emotional dysfunctions linked to activity alterations in the brain, mainly in prefrontal regions, the insula, the anterior cingulate cortex and the amygdala. However, this evidence is heterogeneous, perhaps because magnetic resonance imaging (MRI) studies on MDD tend to neglect comorbid anxiety (COM-A). METHODS: To address this, here a sample of age- and sex-matched patients, nMDD = 90 and nCOM-A = 85, underwent functional MRI to assess neurofunctional group differences during a negative emotional face-matching task using a hypothesis-driven region of interest approach (dorsolateral prefrontal cortex, insula, anterior cingulate cortex, amygdala) and an explorative whole-brain approach. We also assessed these relationships with state-trait anxiety measures, a state depression measure, general functioning and medication load. RESULTS: During face processing, COM-A (compared to MDD) had significantly increased bilateral insula activity. No activity differences were found in the anterior cingulate cortex or the amygdala. Whole-brain analyses revealed increased inferior temporal activation and frontal activation (comprising the inferior and middle frontal gyrus) in COM-A that was positively linked to state anxiety as well as general functioning across groups. LIMITATIONS: Still, the lack of a healthy control and small effects mean this study should be replicated to further interpret the results. CONCLUSIONS: The findings highlight a discriminative activation pattern between MDD and COM-A regarding emotion processing and may present a correlate of potentially anxiety-related psychopathology. In future, further investigations in potential discriminative activity patterns could help to elucidate the origin, development and treatment of depression.

Neural correlates of fear conditioning are associated with treatment-outcomes to behavioral exposure in spider phobia - Evidence from magnetoencephalography.

BACKGROUND: Models of anxiety disorders and the rationale of exposure therapy (ET) are grounded on classical fear conditioning. Yet, it is unclear whether lower fear ratings of conditioned safety versus threat cues and corresponding neural markers of safety-learning and/or fear inhibition assessed before treatment would predict better outcomes of behavioral exposure. METHODS: Sixty-six patients with spider phobia completed pre-treatment clinical and experimental fear conditioning assessments, one session of virtual reality ET, a post-treatment clinical assessment, and a 6-month follow-up assessment. Tilted Gabor gratings served as conditioned stimuli (CS) that were either paired (CS+) or remained unpaired (CS-) with an aversive phobia-related and phobia-unrelated unconditioned stimulus (UCS). CS+/CS- differences in fear ratings and magnetoencephalographic event-related fields (ERFs) were related to percentual symptom reductions from pre- to post-treatment, as assessed via spider phobia questionnaire (SPQ), behavioral avoidance test (BAT), and remission status at 6-month follow-up. RESULTS: We observed no associations between pre-treatment CS+/CS- differences in fear ratings and any treatment outcome. CS+/CS- differences in source estimations of ERFs revealed that higher CS- activity in bilateral dorsolateral prefrontal cortex (dlPFC) was related with SPQ- and BAT-reductions. Associations between CS+/CS- differences and treatment outcomes were also observed in left ventromedial prefrontal cortex (vmPFC) regions, which additionally revealed associations with the follow-up remission status. CONCLUSIONS: Results provide initial evidence that neural pre-treatment CS+/CS- differences may hold predictive information regarding outcomes of behavioral exposure. Our findings highlight a key role of neural responses to safety cues with potentially inhibitory effects on affect-generating structures during fear conditioning.

Changes in brain function during negative emotion processing in the long-term course of depression.

BACKGROUND: Relapses in major depression are frequent and are associated with a high burden of disease. Although short-term studies suggest a normalisation of depression-associated brain functional alterations directly after treatment, long-term investigations are sparse. AIMS: To examine brain function during negative emotion processing in association with course of illness over a 2-year span. METHOD: In this prospective case-control study, 72 in-patients with current depression and 42 healthy controls were investigated during a negative emotional face processing paradigm, at baseline and after 2 years. According to their course of illness during the study interval, patients were divided into subgroups (n = 25 no-relapse, n = 47 relapse). The differential changes in brain activity were investigated by a group × time analysis of covariance for the amygdala, hippocampus, insula and at whole-brain level. RESULTS: A significant relapse × time interaction emerged within the amygdala (PTFCE-FWE = 0.011), insula (PTFCE-FWE = 0.001) and at the whole-brain level mainly in the temporal and prefrontal cortex (PTFCE-FWE = 0.027), resulting from activity increases within the no-relapse group, whereas in the relapse group, activity decreased during the study interval. At baseline, the no-relapse group showed amygdala, hippocampus and insula hypoactivity compared with healthy controls and the relapse group. CONCLUSIONS: This study reveals course of illness-associated activity changes in emotion processing areas. Patients in full remission show a normalisation of their baseline hypo-responsiveness to the activation level of healthy controls after 2 years. Brain function during emotion processing could further serve as a potential predictive marker for future relapse.

Behavioral and Magnetoencephalographic Correlates of Fear Generalization Are Associated With Responses to Later Virtual Reality Exposure Therapy in Spider Phobia.

BACKGROUND: Because overgeneralization of fear is a pathogenic marker of anxiety disorders, we investigated whether pretreatment levels of fear generalization in spider-phobic patients are related to their response to exposure-based treatment to identify pretreatment moderators of treatment success. METHODS: A total of 90 patients with spider phobia completed pretreatment clinical and magnetoencephalography assessments, one session of virtual reality exposure therapy, and a posttreatment clinical assessment. Based on the primary outcome (30% symptom reduction in self-reported symptoms), they were categorized as responders or nonresponders. In a pretreatment magnetoencephalography fear generalization paradigm involving fear conditioning with 2 unconditioned stimuli (UCS), we obtained fear ratings, UCS expectancy ratings, and event-related fields to conditioned stimuli (CS: CS-, CS+) and 7 different generalization stimuli on a perceptual continuum from CS- to CS+. RESULTS: Before treatment, nonresponders showed behavioral overgeneralization indicated by more linear generalization gradients in fear ratings. Analyses of magnetoencephalography source estimations revealed that nonresponders showed a decline of their (inhibitory) frontal activations to safety-signaling CS- and generalization stimuli compared with CS+ over time, while responders maintained these activations at early (<300 ms) and late processing stages. CONCLUSIONS: Results provide initial evidence that pretreatment differences of behavioral and neural markers of fear generalization may act as moderators of later responses to behavioral exposure. Stimulating further research on fear generalization as a potential predictive marker, our findings are an important first step in the attempt to identify patients who may not benefit from exposure therapy and to personalize and optimize treatment strategies for this vulnerable patient group.

Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Systematic transdiagnostic review of magnetic-resonance imaging results: Depression, anxiety disorders and their co-occurrence.

BACKGROUND: Major depressive disorder (MDD) and anxiety disorders (ANX) share core symptoms such as negative affect and often co-exist. Magnetic-resonance imaging (MRI) research suggests shared neuroanatomical/neurofunctional underpinnings. So far, studies considering transdiagnostic and disorder-specific neural alterations in MDD and ANX as well as the comorbid condition (COM) have not been reviewed systematically. METHODS: Following PRISMA guidelines, the literature was screened and N = 247 articles were checked according to the PICOS criteria: MRI studies investigating transdiagnostic (across MDD, ANX, COM compared to healthy controls) and/or disorder-specific (between MDD, ANX, COM) neural alterations. N = 35, thereof n = 13 structural MRI and diffusion-tensor imaging studies and n = 22 functional MRI studies investigating emotional, cognitive deficits and resting state were included and quality coded. RESULTS: Results indicated transdiagnostic structural/functional alterations in the orbitofrontal cortex/middle frontal cortex and in limbic regions (amygdala, cingulum, hippocampus). Few and inconsistent disorder-specific alterations were reported. However, depression-specific functional alterations were reported for the inferior frontal gyrus and dorsolateral prefrontal cortex during emotional tasks, and limbic regions at rest. Preliminary results for anxiety-specific functional alterations were found in the insula and frontal regions during emotional tasks, in the inferior parietal lobule, superior frontal gyrus and superior temporal gyrus during cognitive tasks, and (para)limbic alterations at rest. CONCLUSIONS: This review provides evidence to support existing transdiagnostic fronto-limbic neural models in MDD and ANX. On top, it expands existing knowledge taking into account comorbidity and comparing MDD with ANX. Heterogeneous evidence exists for disorder-specific alterations. Research focusing on ANX sub-types, and the consideration of COM would contribute to a better understanding of basic neural underpinnings.

Neural processing of emotional facial stimuli in specific phobia: An fMRI study.

BACKGROUND: Patients with specific phobia (SP) show altered brain activation when confronted with phobia-specific stimuli. It is unclear whether this pathogenic activation pattern generalizes to other emotional stimuli. This study addresses this question by employing a well-powered sample while implementing an established paradigm using nonspecific aversive facial stimuli. METHODS: N = 111 patients with SP, spider subtype, and N = 111 healthy controls (HCs) performed a supraliminal emotional face-matching paradigm contrasting aversive faces versus shapes in a 3-T magnetic resonance imaging scanner. We performed region of interest (ROI) analyses for the amygdala, the insula, and the anterior cingulate cortex using univariate as well as machine-learning-based multivariate statistics based on this data. Additionally, we investigated functional connectivity by means of psychophysiological interaction (PPI). RESULTS: Although the presentation of emotional faces showed significant activation in all three ROIs across both groups, no group differences emerged in all ROIs. Across both groups and in the HC > SP contrast, PPI analyses showed significant task-related connectivity of brain areas typically linked to higher-order emotion processing with the amygdala. The machine learning approach based on whole-brain activity patterns could significantly differentiate the groups with 73% balanced accuracy. CONCLUSIONS: Patients suffering from SP are characterized by differences in the connectivity of the amygdala and areas typically linked to emotional processing in response to aversive facial stimuli (inferior parietal cortex, fusiform gyrus, middle cingulate, postcentral cortex, and insula). This might implicate a subtle difference in the processing of nonspecific emotional stimuli and warrants more research furthering our understanding of neurofunctional alteration in patients with SP.

Clinical predictors of treatment response towards exposure therapy in virtuo in spider phobia: A machine learning and external cross-validation approach.

While being highly effective on average, exposure-based treatments are not equally effective in all patients. The a priori identification of patients with a poor prognosis may enable the application of more personalized psychotherapeutic interventions. We aimed at identifying sociodemographic and clinical pre-treatment predictors for treatment response in spider phobia (SP). N = 174 patients with SP underwent a highly standardized virtual reality exposure therapy (VRET) at two independent sites. Analyses on group-level were used to test the efficacy. We applied a state-of-the-art machine learning protocol (Random Forests) to evaluate the predictive utility of clinical and sociodemographic predictors for a priori identification of individual treatment response assessed directly after treatment and at 6-month follow-up. The reliability and generalizability of predictive models was tested via external cross-validation. Our study shows that one session of VRET is highly effective on a group-level and is among the first to reveal long-term stability of this treatment effect. Individual short-term symptom reductions could be predicted above chance, but accuracies dropped to non-significance in our between-site prediction and for predictions of long-term outcomes. With performance metrics hardly exceeding chance level and the lack of generalizability in the employed between-site replication approach, our study suggests limited clinical utility of clinical and sociodemographic predictors. Predictive models including multimodal predictors may be more promising.

Childhood maltreatment and cognitive functioning: the role of depression, parental education, and polygenic predisposition.

Childhood maltreatment is associated with cognitive deficits that in turn have been predictive for therapeutic outcome in psychiatric patients. However, previous studies have either investigated maltreatment associations with single cognitive domains or failed to adequately control for confounders such as depression, socioeconomic environment, and genetic predisposition. We aimed to isolate the relationship between childhood maltreatment and dysfunction in diverse cognitive domains, while estimating the contribution of potential confounders to this relationship, and to investigate gene-environment interactions. We included 547 depressive disorder and 670 healthy control participants (mean age: 34.7 years, SD = 13.2). Cognitive functioning was assessed for the domains of working memory, executive functioning, processing speed, attention, memory, and verbal intelligence using neuropsychological tests. Childhood maltreatment and parental education were assessed using self-reports, and psychiatric diagnosis was based on DSM-IV criteria. Polygenic scores for depression and for educational attainment were calculated. Multivariate analysis of cognitive domains yielded significant associations with childhood maltreatment (η²p = 0.083, P < 0.001), depression (η²p = 0.097, P < 0.001), parental education (η²p = 0.085, P < 0.001), and polygenic scores for depression (η²p = 0.021, P = 0.005) and educational attainment (η²p = 0.031, P < 0.001). Each of these associations remained significant when including all of the predictors in one model. Univariate tests revealed that maltreatment was associated with poorer performance in all cognitive domains. Thus, environmental, psychopathological, and genetic risk factors each independently affect cognition. The insights of the current study may aid in estimating the potential impact of different loci of interventions for cognitive dysfunction. Future research should investigate if customized interventions, informed by individual risk profiles and related cognitive preconditions, might enhance response to therapeutic treatments.

Brain functional effects of electroconvulsive therapy during emotional processing in major depressive disorder.

BACKGROUND: In treatment-resistant major depressive disorder (MDD), electroconvulsive therapy (ECT) is a treatment with high efficacy. While knowledge regarding changes in brain structure following ECT is growing, the effects of ECT on brain function during emotional processing are largely unknown. OBJECTIVE: We investigated the effects of ECT on the activity of the anterior cingulate cortex (ACC) and amygdala during negative emotional stimuli processing and its association with clinical response. METHODS: In this non-randomized longitudinal study, patients with MDD (n = 37) were assessed before and after treatment with ECT. Healthy controls (n = 37) were matched regarding age and gender. Functional magnetic resonance imaging (fMRI) was obtained twice, at baseline and after six weeks using a supraliminal face-matching paradigm. In order to evaluate effects of clinical response, additional post-hoc analyses were performed comparing responders to non-responders. RESULTS: After ECT, patients with MDD showed a statistically significant increase in ACC activity during processing of negative emotional stimuli (pFWE = .039). This effect was driven by responders (pFWE = .023), while non-responders showed no increase. Responders also had lower pre-treatment ACC activity compared to non-responders (pFWE = .025). No significant effects in the amygdala could be observed. CONCLUSIONS: ECT leads to brain functional changes in the ACC, a relevant region for emotional regulation during processing of negative stimuli. Furthermore, baseline ACC activity might serve as a biomarker for treatment response. Findings are in accordance with recent studies highlighting properties of pre-treatment ACC to be associated with general antidepressive treatment response.

Replication of a hippocampus specific effect of the tescalcin regulating variant rs7294919 on gray matter structure.

While the hippocampus remains a region of high interest for neuropsychiatric research, the precise contributors to hippocampal morphometry are still not well understood. We and others previously reported a hippocampus specific effect of a tescalcin gene (TESC) regulating single nucleotide polymorphism (rs7294919) on gray matter volume. Here we aimed to replicate and extend these findings. Two complementary morphometric approaches (voxel based morphometry (VBM) and automated volumetric segmentation) were applied in a well-powered cohort from the Marburg-Münster Affective Disorder Cohort Study (MACS) including N=1137 participants (n=636 healthy controls, n=501 depressed patients). rs7294919 homozygous T-allele genotype was significantly associated with lower hippocampal gray matter density as well as with reduced hippocampal volume. Exploratory whole brain VBM analyses revealed no further associations with gray matter volume outside the hippocampus. No interaction effects of rs7294919 with depression nor with childhood trauma on hippocampal morphometry could be detected. Hippocampal subfield analyses revealed similar effects of rs7294919 in all hippocampal subfields. In sum, our results replicate a hippocampus specific effect of rs7294919 on brain structure. Due to the robust evidence for a pronounced association between the reported polymorphism and hippocampal morphometry, future research should consider investigating the potential clinical and functional relevance of the reported association.

Extending the vulnerability-stress model of mental disorders: three-dimensional NPSR1 × environment × coping interaction study in anxiety.

BACKGROUND: The general understanding of the 'vulnerability-stress model' of mental disorders neglects the modifying impact of resilience-increasing factors such as coping ability. AIMS: Probing a conceptual framework integrating both adverse events and coping factors in an extended 'vulnerability-stress-coping model' of mental disorders, the effects of functional neuropeptide S receptor gene (NPSR1) variation (G), early adversity (E) and coping factors (C) on anxiety were addressed in a three-dimensional G × E × C model. METHOD: In two independent samples of healthy probands (discovery: n = 1403; replication: n = 630), the interaction of NPSR1 rs324981, childhood trauma (Childhood Trauma Questionnaire, CTQ) and general self-efficacy as a measure of coping ability (General Self-Efficacy Scale, GSE) on trait anxiety (State-Trait Anxiety Inventory) was investigated via hierarchical multiple regression analyses. RESULTS: In both samples, trait anxiety differed as a function of NPSR1 genotype, CTQ and GSE score (discovery: ß = 0.129, P = 3.938 × 10-8; replication: ß = 0.102, P = 0.020). In A allele carriers, the relationship between childhood trauma and anxiety was moderated by general self-efficacy: higher self-efficacy and childhood trauma resulted in low anxiety scores, and lower self-efficacy and childhood trauma in higher anxiety levels. In turn, TT homozygotes displayed increased anxiety as a function of childhood adversity unaffected by general self-efficacy. CONCLUSIONS: Functional NPSR1 variation and childhood trauma are suggested as prime moderators in the vulnerability-stress model of anxiety, further modified by the protective effect of self-efficacy. This G × E × C approach - introducing coping as an additional dimension further shaping a G × E risk constellation, thus suggesting a three-dimensional 'vulnerability-stress-coping model' of mental disorders - might inform targeted preventive or therapeutic interventions strengthening coping ability to promote resilient functioning.

Cortical surface area alterations shaped by genetic load for neuroticism.

Neuroticism has been shown to act as an important risk factor for major depressive disorder (MDD). Genetic and neuroimaging research has independently revealed biological correlates of neurotic personality including cortical alterations in brain regions of high relevance for affective disorders. Here we investigated the influence of a polygenic score for neuroticism (PGS) on cortical brain structure in a joint discovery sample of n = 746 healthy controls (HC) and n = 268 MDD patients. Findings were validated in an independent replication sample (n = 341 HC and n = 263 MDD). Subgroup analyses stratified for case-control status and analyses of associations between neurotic phenotype and cortical measures were carried out. PGS for neuroticism was significantly associated with a decreased cortical surface area of the inferior parietal cortex, the precuneus, the rostral cingulate cortex and the inferior frontal gyrus in the discovery sample. Similar associations between PGS and surface area of the inferior parietal cortex and the precuneus were demonstrated in the replication sample. Subgroup analyses revealed negative associations in the latter regions between PGS and surface area in both HC and MDD subjects. Neurotic phenotype was negatively correlated with surface area in similar cortical regions including the inferior parietal cortex and the precuneus. No significant associations between PGS and cortical thickness were detected. The morphometric overlap of associations between both PGS and neurotic phenotype in similar cortical regions closely related to internally focused cognition points to the potential relevance of genetically shaped cortical alterations in the development of neuroticism.

Influence of electroconvulsive therapy on white matter structure in a diffusion tensor imaging study.

BACKGROUND: Electroconvulsive therapy (ECT) is a fast-acting intervention for major depressive disorder. Previous studies indicated neurotrophic effects following ECT that might contribute to changes in white matter brain structure. We investigated the influence of ECT in a non-randomized prospective study focusing on white matter changes over time. METHODS: Twenty-nine severely depressed patients receiving ECT in addition to inpatient treatment, 69 severely depressed patients with inpatient treatment (NON-ECT) and 52 healthy controls (HC) took part in a non-randomized prospective study. Participants were scanned twice, approximately 6 weeks apart, using diffusion tensor imaging, applying tract-based spatial statistics. Additional correlational analyses were conducted in the ECT subsample to investigate the effects of seizure duration and therapeutic response. RESULTS: Mean diffusivity (MD) increased after ECT in the right hemisphere, which was an ECT-group-specific effect. Seizure duration was associated with decreased fractional anisotropy (FA) following ECT. Longitudinal changes in ECT were not associated with therapy response. However, within the ECT group only, baseline FA was positively and MD negatively associated with post-ECT symptomatology. CONCLUSION: Our data suggest that ECT changes white matter integrity, possibly reflecting increased permeability of the blood-brain barrier, resulting in disturbed communication of fibers. Further, baseline diffusion metrics were associated with therapy response. Coherent fiber structure could be a prerequisite for a generalized seizure and inhibitory brain signaling necessary to successfully inhibit increased seizure activity.

Theranostic markers for personalized therapy of spider phobia: Methods of a bicentric external cross-validation machine learning approach.

OBJECTIVES: Embedded in the Collaborative Research Center "Fear, Anxiety, Anxiety Disorders" (CRC-TRR58), this bicentric clinical study aims at identifying biobehavioral markers of treatment (non-)response by applying machine learning methodology with an external cross-validation protocol. We hypothesize that a priori prediction of treatment (non-)response is possible in a second, independent sample based on multimodal markers. METHODS: One-session virtual reality exposure treatment (VRET) with patients with spider phobia was conducted on two sites. Clinical, neuroimaging, and genetic data were assessed at baseline, post-treatment and after 6 months. The primary and secondary outcomes defining treatment response are as follows: 30% reduction regarding the individual score in the Spider Phobia Questionnaire and 50% reduction regarding the individual distance in the behavioral avoidance test. RESULTS: N = 204 patients have been included (n = 100 in Würzburg, n = 104 in Münster). Sample characteristics for both sites are comparable. DISCUSSION: This study will offer cross-validated theranostic markers for predicting the individual success of exposure-based therapy. Findings will support clinical decision-making on personalized therapy, bridge the gap between basic and clinical research, and bring stratified therapy into reach. The study is registered at ClinicalTrials.gov (ID: NCT03208400).

Affective temperaments (TEMPS-A) in panic disorder and healthy probands: Genetic modulation by 5-HTT variation.

OBJECTIVES: Temperamental traits as ascertained by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto-Questionnaire (TEMPS-A) have been suggested as promising intermediate phenotypes of mental disorders. In anxiety disorders, however, TEMPS scales and their genetic underpinnings are still understudied. METHODS: TEMPS-A scores in 109 patients with panic disorder (PD) were compared to a sample of 536 healthy probands. All participants were genotyped for serotonin transporter gene variation (5-HTTLPR/rs25531). RESULTS: PD patients displayed significantly increased scores on the dysthymic, cyclothymic, irritable and anxious subscales, and lower scores on the hyperthymic subscale, respectively (all ps < 0.001) compared to healthy probands. In the total sample, the less active 5-HTTLPR/rs25531 S/LG alleles were associated with higher scores on the dysthymic, cyclothymic, irritable and anxious temperaments (all ps < 0.01), but not the hyperthymic subscale. Mediation analyses revealed anxious temperament in particular to mediate the relationship between 5-HTT genotype and PD. CONCLUSIONS: Dysthymic, cyclothymic, irritable and notably anxious temperament could serve as valuable intermediate phenotypes in efforts to unravel neurobiological, particularly serotonin system related genetic pathomechanisms associated with PD and potentially contribute to a panel of vulnerability markers guiding early targeted preventive interventions.

Factors influencing the success of exposure therapy for specific phobia: A systematic review.

Although Exposure Therapy (ET) is the first-line treatment of Specific Phobia (SP), there is no clear consensus on which factors influence its success, and thus on how to conduct it most efficiently. This review summarizes the current state of research regarding this topic. N = 111 studies were in accordance with our eligibility criteria: participants had at least symptoms of SP, the intervention was ET and the study investigated a factor influencing its success. Best evidence for positive effects was found for low trait anxiety, high motivation and high self-efficacy before the ET, high cortisol levels and heart rate variation, evoking disgust additionally to anxiety, avoiding relaxation, focusing on cognitive changes, context variation, sleep, and memory-enhancing drugs. These factors may be conceptualized as modulating different aspects of learning as suggested in current models of ET that focus on inhibitory learning mechanisms. Limitations lie in the great heterogeneity concerning operationalization of factors and success. Based on these findings, we make suggestions for improvements in ET conduction and which factors should be researched in the future.

Reduced fractional anisotropy in depressed patients due to childhood maltreatment rather than diagnosis.

Reduced fractional anisotropy (FA) associated with Major Depressive Disorder (MDD) overlaps anatomically with effects of childhood maltreatment experiences. The aim of this study was, therefore, to replicate the negative effect of childhood maltreatment on white matter fiber structure and to demonstrate, that alterations in MDD might be partially attributed to the higher occurrence of childhood maltreatment in MDD. Two independent cohorts (total N = 1 256) were investigated in a diffusion tensor imaging study: The Münster Neuroimaging Cohort (MNC, N = 186 MDD, N = 210 healthy controls, HC) as discovery sample and the Marburg-Münster Affective Disorders Cohort Study (MACS, N = 397 MDD, N = 462 HC) as replication sample. The effects of diagnosis (HC vs. MDD) and Childhood Trauma Questionnaire (CTQ) scores on FA were analyzed. A main effect of diagnosis with higher FA in MDD patients compared with HC was found in the MNC (pFWE = 0.021), but not in the MACS (pFWE = 0.52) before correcting for CTQ. A significant negative correlation of FA with CTQ emerged in both cohorts (MNC: pFWE = 0.006, MACS: pFWE = 0.012) in several tracts previously described in the literature. No CTQ × diagnosis interaction could be detected. Any main effect of diagnosis was abolished after correcting for CTQ (MNC: pFWE = 0.562, MACS: pFWE = 0.115). No differences in FA between MDD and HC could be found after correcting for childhood maltreatment, suggesting that previously reported group differences might be attributed partially to higher levels of maltreatment experiences in MDD rather than diagnosis itself. Furthermore, a well-established finding of reduced FA following childhood maltreatment experiences was replicated.