Theta burst stimulation add on to dialectical behavioral therapy in borderline-personality-disorder: methods and design of a randomized, single-blind, placebo-controlled pilot trial.

Specialized psychotherapeutic treatments like dialectical behavioral therapy (DBT) are recommended as first treatment for borderline personality disorder (BPD). In recent years, studies have emerged that focus on repetitive transcranial magnetic stimulation (rTMS) in BPD. Both have independently demonstrated efficacy in the treatment of BPD. Intermitted theta burst stimulation (iTBS), a modified design of rTMS, is thought to increase the excitability of neurons and could be a supplement to psychotherapy in addition to being a standalone treatment. However, no studies to date have investigated the combination of DBT and rTMS/iTBS. This study protocol describes the methods and design of a randomized, single-blinded, sham-controlled clinical pilot study in which BPD patients will be randomly assigned to either iTBS or sham during four consecutive weeks (20 sessions in total) in addition to standardized DBT treatment. The stimulation will focus on the unilateral stimulation of the left dorsolateral prefrontal cortex (DLPFC), which plays an important role in the control of impulsivity and risk-taking. Primary outcome is the difference in borderline symptomatology, while secondary target criteria are depressive symptoms, general functional level, impulsivity and self-compassion. Statistical analysis of therapy response will be conducted by Mixed Model Repeated Measurement using a 2 × 2-factorial between-subjects design with the between-subject factor stimulation (TMS vs. Sham) and the within-subject factor time (T0 vs. T1). Furthermore, structural magnetic resonance imaging (MRI) will be conducted and analyzed. The study will provide evidence and insight on whether iTBS has an enhancing effect as add-on to DBT in BPD.Trial registration: drks.de (DRKS00020413) registered 13/01/2020.

Influence of motivational placebo-related factors on the effects of exercise treatment in depressive adolescents.

Recent meta-analyses reveal a moderate effect of physical activity (PA) in the treatment of adolescent depression. However, not only the underlying neurobiological mechanisms, also the influences of placebo-related motivational factors (beliefs and expectancies in sporting, enjoyment and prior sports experiences), are still unclear. Based on the data of our prior study "Mood Vibes", we hypothesized that placebo-inherent factors like positive prior sports experiences and motivational factors, (positive beliefs, expectancies, and enjoyment related to PA), would increase the effects of an add-on exercise-therapy in juvenile depression. From 64 included depressed adolescents, 41 underwent an intensive add-on PA-therapy. Motivational factors were assessed using sport-specific scales. The changes in depression scores under treatment were rated by self-rating scale (German "Childhood Depression Inventory", (DIKJ)). A mixed model for repeated measures (MMRM) was used to analyze the effects of the different motivational variates on DIKJ. While prior sports experiences had no impact, motivational factors showed a significant effect on PA-induced changes in DIKJ scores (p = 0.002). The demotivated participants improved less, whereas it was sufficient to be neutral towards sporting to benefit significantly more. Motivational placebo-related factors (beliefs, expectancies and enjoyment regarding PA) affected the outcomes of an exercise treatment in depressed adolescents. Yet, a neutral mindset was sufficient to profit more from PA. Prior sporting in the sense of positive conditioning and as a protective factor did not play a role. Knowledge about these influences could in a second step help to develop tailored therapies.

Arbitration between insula and temporoparietal junction subserves framing-induced boosts in generosity during social discounting.

Generosity toward others declines across the perceived social distance to them. Here, participants chose between selfish and costly generous options in two conditions: in the gain frame, a generous choice yielded a gain to the other; in the loss frame, it entailed preventing the loss of a previous endowment to the other. Social discounting was reduced in the loss compared to the gain frame, implying increased generosity toward strangers. Using neuroimaging tools, we found that while activity in the temporoparietal junction (TPJ) and the ventromedial prefrontal cortex (VMPFC) was associated with generosity in the gain frame, the insular cortex was selectively recruited during generous choices in the loss frame. We provide support for a network-model according to which TPJ and insula differentially subserve generosity by modulating value signals in the VMPFC in a frame-dependent fashion. These results extend our understanding of the insula role in nudging prosocial behavior in humans.

Serotonergic influence on depressive symptoms and trait anxiety is mediated by negative life events and frontal activation in children and adolescents.

Depression and anxiety are common in childhood and adolescence. Even though cardinal symptoms differ, there is a considerable overlap regarding the pathogenic influence of serotonergic innervation, negative life experience, disturbed emotion perception/affect regulation, and impaired neural functioning in the fronto-limbic circuit. In this study, we examined the effect of the 5-HTTLPR/rs25531 genotype on depressive symptoms and trait anxiety under the consideration of the amount of negative life events in healthy children and adolescents (N = 389). In a subsample of 49 subjects, we performed fMRI to add fronto-limbic brain activation as a second interacting factor. Across all subjects, negative life events moderated the influence of the 5-HTTLPR/rs25531 genotype on both depressive symptoms and trait anxiety. In the fMRI subsample, 5-HTTLPR/rs25531 S + S/LG + S/LA + LGLA + LGLG genotype-associated left middle frontal gyrus (MFG) activation mediated the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms, however, only in combination with negative life events. Genetic influence on trait anxiety was predominantly mediated by negative life events; only LALA genotype-specific activation in the right MFG worked as a mediator in combination with negative life events. The present findings hint towards distinct mechanisms mediating the influence of 5-HTTLPR/rs25531 genotype on depressive symptoms and anxiety, with negative life events playing a crucial role in both phenotypes. With regard to depressive symptoms, however, this influence was only visible in combination with MFG activation, whereas, in anxiety, it was independent of brain activation.

Cognitive-behavioral therapy effects on alerting network activity and effective connectivity in panic disorder.

Given the particular relevance of arousal and alerting in panic disorder (PD), here the alerting network was investigated (1) contrasting patients with PD and healthy controls, (2) as a function of anxiety sensitivity constituting a dimensional measure of panic-related anxiety, and (3) as a possible correlate of treatment response. Using functional magnetic resonance imaging (fMRI), 45 out-patients with PD (f = 34) and 51 matched healthy controls were investigated for brain activation patterns and effective connectivity (Dynamic Causal Modeling, DCM) while performing the Attention Network Task (ANT). Anxiety sensitivity was ascertained by the Anxiety Sensitivity Index (ASI). Forty patients and 48 controls were re-scanned after a 6 weeks cognitive-behavioral treatment (CBT) or an equivalent waiting time, respectively. In the alerting condition, patients showed decreased activation in fronto-parietal pathways including the middle frontal gyrus and the superior parietal lobule (MFG, SPL). In addition, ASI scores were negatively correlated with connectivity emerging from the SPL, the SFB and the LC and going to the MFG in patients but not in healthy controls. CBT resulted in an increase in middle frontal and parietal activation along with increased connectivity going from the MFG to the SPL. This change in connectivity was positively correlated with reduction in ASI scores. There were no changes in controls. The present findings point to a pathological disintegration of the MFG in a fronto-parietal pathway in the alerting network in PD which was observed to be reversible by a successful CBT intervention.

Neuropeptide S Receptor Gene Variation Differentially Modulates Fronto-Limbic Effective Connectivity in Childhood and Adolescence.

The neuropeptide S (NPS) system contributes to the pathogenesis of anxiety. The more active T allele of the functional rs324981 variant in the neuropeptide S receptor gene (NPSR1) is associated with panic disorder (PD) and distorted cortico-limbic activity during emotion processing in healthy adults and PD patients. This study investigated the influence of NPSR1 genotype on fronto-limbic effective connectivity within the developing brain. Sixty healthy subjects (8-21 years) were examined using an emotional go-nogo task and fMRI. Fronto-limbic connectivity was determined using Dynamic Causal Modeling. In A allele carriers, connectivity between the right middle frontal gyrus (MFG) and the right amygdala was higher in older (≥14 years) than that in younger (<14 years) probands, whereas TT homozygotes ≥14 years showed a reduction of fronto-limbic connectivity between the MFG and both the amygdala and the insula. Fronto-limbic connectivity varied between NPSR1 genotypes in the developing brain suggesting a risk-increasing effect of the NPSR1T allele for anxiety-related traits via impaired top-down control of limbic structures emerging during adolescence. Provided robust replication in longitudinal studies, these findings may constitute valuable biomarkers for early targeted prevention of anxiety disorders.

Modulation of prefrontal functioning in attention systems by NPSR1 gene variation.

Evidence has accumulated for a dysfunction of arousal and executive attention in anxiety. The neuropeptide S (NPS) system has been shown to play a pivotal role in the mediation of arousal and to be associated with anxiety/panic disorder. The present study aims at investigating the impact of functional neuropeptide S receptor (NPSR1) gene variation on neural attention patterns applying an imaging genetics approach. In an event-related functional magnetic resonance imaging (fMRI) setting, 47 healthy subjects (f=23) evenly pre-stratified for NPSR1 rs324981 A/T genotype were investigated for brain activation patterns while performing the Attention Network Task (ANT), simultaneously probing alerting and executive control functions. Anxiety sensitivity was ascertained by the Anxiety Sensitivity Index (ASI). In the alerting condition, NPSR1 TT homozygotes showed higher activations in the right prefrontal cortex and the locus coeruleus region as compared to A allele carriers. In the executive control condition, TT homozygotes displayed increased activations in fronto-parietal regions. Genotype-driven activation differences in the prefrontal cortex correlated with anxiety sensitivity, in both the alerting and the executive control system. The present results for the first time suggest NPSR1 gene variation to be associated with alterations of prefrontal functioning in the attentional functions alerting and executive control partly modulated by anxiety sensitivity. These findings may aid in unraveling the neurobiological underpinnings of distorted arousal and attention in anxiety and thereby possibly in the biomarker-guided development of preventive/therapeutic strategies targeting attention processes in anxiety disorders.

Predicting effective connectivity from resting-state networks in healthy elderly and patients with prodromal Alzheimer's disease.

Using functional neuroimaging techniques two aspects of functional integration in the human brain have been investigated, functional connectivity and effective connectivity. In this study we examined both connectivity types in parallel within an executive attention network during rest and while performing an attention task. We analyzed the predictive value of resting-state functional connectivity on task-induced effective connectivity in patients with prodromal Alzheimer's disease (AD) and healthy elderly. We found that in healthy elderly, functional connectivity was a significant predictor for effective connectivity, however, it was frequency-specific. Effective top-down connectivity emerging from prefrontal areas was related with higher frequencies of functional connectivity (e.g., 0.08-0.15 Hz), in contrast to effective bottom-up connectivity going to prefrontal areas, which was related to lower frequencies of functional connectivity (e.g., 0.001-0.03 Hz). In patients, the prediction of effective connectivity by functional connectivity was disturbed. We conclude that functional connectivity and effective connectivity are interrelated in healthy brains but this relationship is aberrant in very early AD.

Arousal and the attentional network in panic disorder.

Although a great deal of information about the neurobiology of panic disorder is now available, there is a need for an updated etiological model integrating recent findings on the neurobiology of the arousal system and its relationship with higher cortical functions in panic disorder. The current mini-review presents psychophysiological, molecular biological/genetic and functional neuroimaging evidence for dysfunction in major arousal systems of the brain. Such dysfunction may influence the development of panic disorder by precipitating autonomic bodily symptoms and at the same time increasing vigilance to these sensations by modulating cortical attentional networks. A multilevel model of arousal, attention and anxiety-including the norepinephrine, orexin, neuropeptide S and caffeine-related adenosine systems-may be useful in integrating a range of data available on the pathogenesis of panic disorder.

Simultaneous electroencephalographic and functional magnetic resonance imaging indicate impaired cortical top-down processing in association with anesthetic-induced unconsciousness.

BACKGROUND: In imaging functional connectivity (FC) analyses of the resting brain, alterations of FC during unconsciousness have been reported. These results are in accordance with recent electroencephalographic studies observing impaired top-down processing during anesthesia. In this study, simultaneous records of functional magnetic resonance imaging (fMRI) and electroencephalogram were performed to investigate the causality of neural mechanisms during propofol-induced loss of consciousness by correlating FC in fMRI and directional connectivity (DC) in electroencephalogram. METHODS: Resting-state 63-channel electroencephalogram and blood oxygen level-dependent 3-Tesla fMRI of 15 healthy subjects were simultaneously registered during consciousness and propofol-induced loss of consciousness. To indicate DC, electroencephalographic symbolic transfer entropy was applied as a nonlinear measure of mutual interdependencies between underlying physiological processes. The relationship between FC of resting-state networks of the brain (z values) and DC was analyzed by a partial correlation. RESULTS: Independent component analyses of resting-state fMRI showed decreased FC in frontoparietal default networks during unconsciousness, whereas FC in primary sensory networks increased. DC indicated a decline in frontal-parietal (area under the receiver characteristic curve, 0.92; 95% CI, 0.68-1.00) and frontooccipital (0.82; 0.53-1.00) feedback DC (P<0.05 corrected). The changes of FC in the anterior default network correlated with the changes of DC in frontal-parietal (rpartial=+0.62; P=0.030) and frontal-occipital (+0.63; 0.048) electroencephalographic electrodes (P<0.05 corrected). CONCLUSION: The simultaneous propofol-induced suppression of frontal feedback connectivity in the electroencephalogram and of frontoparietal FC in the fMRI indicates a fundamental role of top-down processing for consciousness.

Serotonergic modulation of normal and abnormal brain dynamics: The genetic influence of the TPH2 G-703T genotype and DNA methylation on wavelet variance in children and adolescents with and without ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persists into adulthood. Core symptoms of ADHD, such as impulsivity, are caused by an interaction of genetic and environmental factors. Epigenetic modifications of DNA, such as DNA methylation, are thought to mediate the interplay of these factors. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin synthesis. The TPH2 gene has frequently been investigated in relation to ADHD, e.g., showing that TPH2 G-703T (rs4570625) polymorphism influences response control and prefrontal signaling in ADHD patients. In this (epi)genetic imaging study we examined 144 children and adolescents (74 patients, 14 females) using fMRI at rest and during performing a waiting impulsivity (WI) paradigm. Both, TPH2 G-703T (rs4570625) genotype and DNA methylation in the 5' untranslated region (5'UTR) of TPH2 were associated with wavelet variance in fronto-parietal regions and behavioral performance, taking TPH2 genotype into account. In detail, comparisons between genotypes of patients and controls revealed highest wavelet variance and longest reaction times in patients carrying the T allele [indicative for a gene-dosage effect, i.e., the WI phenotype is a direct result of the cumulative effect of ADHD and TPH2 variation]. Regressions revealed a significant effect on one specific DNA methylation site in ADHD patients but not controls, in terms of a significant prediction of wavelet variance in fronto-parietal regions as well as premature responses. By the example of the TPH2 G-703T (rs4570625) polymorphism, we provide insight into how interactive genetic and DNA methylation affect the ADHD and/or impulsive endophenotype.

Clinical, Brain, and Multilevel Clustering in Early Psychosis and Affective Stages.

Importance: Approaches are needed to stratify individuals in early psychosis stages beyond positive symptom severity to investigate specificity related to affective and normative variation and to validate solutions with premorbid, longitudinal, and genetic risk measures. Objective: To use machine learning techniques to cluster, compare, and combine subgroup solutions using clinical and brain structural imaging data from early psychosis and depression stages. Design, Setting, and Participants: A multisite, naturalistic, longitudinal cohort study (10 sites in 5 European countries; including major follow-up intervals at 9 and 18 months) with a referred patient sample of those with clinical high risk for psychosis (CHR-P), recent-onset psychosis (ROP), recent-onset depression (ROD), and healthy controls were recruited between February 1, 2014, to July 1, 2019. Data were analyzed between January 2020 and January 2022. Main Outcomes and Measures: A nonnegative matrix factorization technique separately decomposed clinical (287 variables) and parcellated brain structural volume (204 gray, white, and cerebrospinal fluid regions) data across CHR-P, ROP, ROD, and healthy controls study groups. Stability criteria determined cluster number using nested cross-validation. Validation targets were compared across subgroup solutions (premorbid, longitudinal, and schizophrenia polygenic risk scores). Multiclass supervised machine learning produced a transferable solution to the validation sample. Results: There were a total of 749 individuals in the discovery group and 610 individuals in the validation group. Individuals included those with CHR-P (n = 287), ROP (n = 323), ROD (n = 285), and healthy controls (n = 464), The mean (SD) age was 25.1 (5.9) years, and 702 (51.7%) were female. A clinical 4-dimensional solution separated individuals based on positive symptoms, negative symptoms, depression, and functioning, demonstrating associations with all validation targets. Brain clustering revealed a subgroup with distributed brain volume reductions associated with negative symptoms, reduced performance IQ, and increased schizophrenia polygenic risk scores. Multilevel results distinguished between normative and illness-related brain differences. Subgroup results were largely validated in the external sample. Conclusions and Relevance: The results of this longitudinal cohort study provide stratifications beyond the expression of positive symptoms that cut across illness stages and diagnoses. Clinical results suggest the importance of negative symptoms, depression, and functioning. Brain results suggest substantial overlap across illness stages and normative variation, which may highlight a vulnerability signature independent from specific presentations. Premorbid, longitudinal, and genetic risk validation suggested clinical importance of the subgroups to preventive treatments.

Immunological Effects of an Add-On Physical Exercise Therapy in Depressed Adolescents and Its Interplay with Depression Severity.

BACKGROUND: Pro-inflammatory cytokines (PICs) have gained attention in the pathophysiology and treatment of depressive disorders. At the same time, the therapeutic effect of physical activity seems to work via immunomodulatory pathways. The interventional study "Mood Vibes" analyzed the influence of exercise on depression severity (primary endpoint) in depressive adolescents; the influence of PICs on the clinical outcome was analyzed as a secondary endpoint. METHODS: Clinically diagnosed depressed adolescents (N = 64; 28.1% male; mean age = 15.9; mean BMI = 24.6) were included and participated either in Whole Body Vibration (WBV) (n = 21) or bicycle ergometer training (n = 20) in addition to treatment-as-usual (TAU). Patients in the control treatment group received TAU only (n = 23). The PICs (interleukin-6-IL-6 and tumor necrosis factor-α-TNF-α) were analyzed before intervention, after 6 weeks of training (t1), and 8 weeks post-intervention (t2). The effects of the treatment on depression severity were rated by self-rating "Depression Inventory for Children and Adolescents" (DIKJ). RESULTS: Basal IL-6 decreased in all groups from t0 to t1, but it increased again in WBV and controls at t2. TNF-α diminished in ergometer and controls from baseline to t1. PIC levels showed no correlation with depression severity at baseline. The influence on DIKJ scores over time was significant for IL-6 in the WBV group (p = 0.008). Sex had an impact on TNF-α (p < 0.001), with higher concentrations in male patients. Higher body mass index was associated with higher IL-6 concentrations over all measurement points (p < 0.001). CONCLUSIONS: The positive effects of an intensive add-on exercise therapy on adolescent depression seem to be partly influenced by immunomodulation. A small sample size and non-randomized controls are limitations of this study.

The cognitive anxiety sensitivity treatment (CAST) in anxiety prevention - Focus on separation anxiety and interoception.

Given the high prevalence and considerable clinical and societal burden of anxiety disorders, preventive measures are urgently warranted to reduce their incidence and overall healthcare impact. Anxiety sensitivity (AS) - a key element in learning theories of anxiety disorders in the context of interoceptive conditioning - constitutes a malleable risk factor of particularly panic disorder and separation anxiety, which share developmental, nosological, epidemiological and pathomechanistic characteristics. The computer-assisted 'Cognitive Anxiety Sensitivity Treatment' (CAST) targeting interoceptive anxiety symptoms (cf. Schmidt et al., 2014) was translated, intensified and culturally adapted to German and evaluated in a sample of 105 healthy adult volunteers with elevated AS (mean ASI-3: 29.5) applying a randomized design. Success of the intervention was measured as a function of AS and separation anxiety (ASA-27) ∼6 weeks (T1) and ∼6 months (T2) after the intervention. As compared to waitlist, CAST resulted in a significant reduction of AS at both T1 and T2. Separation anxiety was not directly reduced by the intervention, but decreased mediated by a decline in AS. A composite interoceptive score capturing changes in sensitivity to respiratory symptoms during the baseline therapist-accompanied CAST session was shown to be predictive of overall response at T1. In sum, CAST-German Version was successfully established as an effective intervention reducing AS, while at the same time indirectly decreasing separation anxiety. A composite interoceptive score predicting treatment response might aid in further delineating risk markers informing targeted preventive interventions for anxiety disorders.

REVERSE phenotyping-Can the phenotype following constitutive Tph2 gene inactivation in mice be transferred to children and adolescents with and without adhd?

INTRODUCTION: Experimental models of neuropsychiatric disorders, for example, ADHD, are used to mimic specific phenotypic traits of a complex human disorder. However, it remains unresolved to what extent the animal phenotype reflects the specific human trait. The null mutant mouse of the serotonin-synthesizing tryptophan hydroxylase-2 (Tph2-/- ) gene has been proposed as experimental model for ADHD with high face validity for impulsive, aggressive, and anxious behaviors. To validate this ADHD-like model, we examined the Tph2-/- phenotype in humans when considering allelic variation of TPH2 function ("reverse phenotyping"). METHODS: 58 participants (6 females, 8-18 years) were examined, of whom 32 were diagnosed with ADHD. All participants were phenotyped for impulsivity, aggression, and anxiety using questionnaires, behavioral tests, and MRI scanning while performing the 4-choice serial reaction time task. Additionally, participants were genotyped for the TPH2 G-703T (rs4570625) polymorphism. To analyze the relation between TPH2 G-703T variants and the impulsive/aggressive/anxious phenotype, mediation analyses were performed using behavioral and MRI data as potential mediators. RESULTS: We found that the relation between TPH2 G-703T and aggression as part of the reverse Tph2- /- phenotype was mediated by structure and function of the right middle and inferior frontal gyrus. CONCLUSION: At the example of trait aggression, our results support the assumption that the Tph2 null mutant mouse reflects the TPH2 G-703T-dependent phenotype in humans. Additionally, we conclude that "reverse phenotyping" is a promising method to validate experimental models and human findings for refined analysis of disease mechanisms.

Multimodal Machine Learning Workflows for Prediction of Psychosis in Patients With Clinical High-Risk Syndromes and Recent-Onset Depression.

Importance: Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear. Objectives: To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models' geographic generalizability; to test and integrate clinicians' predictions; and to maximize clinical utility by building a sequential prognostic system. Design, Setting, and Participants: This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020. Main Outcomes and Measures: Accuracy and generalizability of prognostic systems. Results: A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results. Conclusions and Relevance: These findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms' and clinicians' risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation.

Sex differences and the impact of steroid hormones on the developing human brain.

Little is known about the hormonal effects of puberty on the anatomy of the developing human brain. In a voxel-based morphometry study, sex-related differences in gray matter (GM) volume were examined in 46 subjects aged 8-15 years. Males had larger GM volumes in the left amygdala, whereas females had larger right striatal and bilateral hippocampal GM volumes than males. Sexually dimorphic areas were related to Tanner stages (TS) of pubertal development and to circulating level of steroid hormones in a subsample of 30 subjects. Regardless of sex, amygdala and hippocampal volumes varied as a function of TS and were associated with circulating testosterone (TEST) levels. By contrast, striatal GM volumes were unrelated to pubertal development and circulating steroid hormones. Whole-brain regression analyses revealed positive associations between circulating estrogen levels and parahippocampal GM volumes as well as between TEST levels and diencephalic brain structures. In addition, a negative association was found between circulating TEST and left parietal GM volumes. These data suggest that GM development in certain brain regions is associated with sexual maturation and that pubertal hormones might have organizational effects on the developing human brain.

Regional Hurst Exponent Reflects Impulsivity-Related Alterations in Fronto-Hippocampal Pathways Within the Waiting Impulsivity Network.

In general, the Hurst exponent. is used as a measure of long-term memory of time series. In previous neuroimaging studies, H has been introduced as one important parameter to define resting-state networks, reflecting upon global scale-free properties emerging from a network. H has been examined in the waiting impulsivity (WI) network in an earlier study. We found that alterations of H in the anterior cingulate cortex (H A C C ) and the nucleus accumbens (H N A c c ) were lower in high impulsive (highIMP) compared to low impulsive (lowIMP) participants. Following up on those findings, we addressed the relation between altered fractality in H A C C and H N A c c and brain activation and neural network connectivity. To do so, brain activation maps were calculated, and network connectivity was determined using the Dynamic Causal Modeling (DCM) approach. Finally, 1-H scores were determined to quantify the alterations of H. This way, the focus of the analyses was placed on the potential effects of alterations of H on neural network activation and connectivity. Correlation analyses between the alterations of H A C C /H N A c c and activation maps and DCM estimates were performed. We found that the alterations of H predominantly correlated with fronto-hippocampal pathways and correlations were significant only in highIMP subjects. For example, alterations of H A C C was associated with a decrease in neural activation in the right HC in combination with increased ACC-hippocampal connectivity. Alteration inH N A c c , in return, was related to an increase in bilateral prefrontal activation in combination with increased fronto-hippocampal connectivity. The findings, that the WI network was related to H alteration in highIMP subjects indicated that impulse control was not reduced per se but lacked consistency. Additionally, H has been used to describe long-term memory processes before, e.g., in capital markets, energy future prices, and human memory. Thus, current findings supported the relation of H toward memory processing even when further prominent cognitive functions were involved.

Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes.

Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10-7), particularly in the female subsample (p = 9.8 × 10-9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10-4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.

Developmental changes in neural activation and psychophysiological interaction patterns of brain regions associated with interference control and time perception.

Interference control and time perception are mediated by common neural networks, including the frontal and parietal lobes, the cerebellum and the basal ganglia. Previous studies have shown that while time perception develops early in life, interference control seems to follow a protracted course of maturation into late adolescence. Thus, the current study examined developmental changes in neural activation and functional interaction between brain regions during a combined time discrimination and interference control task using fMRI. Thirty-four participants, aged 8-15 years, were scanned while performing a spatial stimulus response compatibility (SRC) task and a time discrimination (TD) task using identical stimuli. We found shared neural activation in a fronto-parieto-cerebellar network as well as task-specific patterns of psychophysiological interaction with positive coupling between the right inferior frontal gyrus (IFG), the superior parietal lobes bilaterally, the contralateral IFG and the thalamus during interference control and positive interactions between the right IFG and bilateral cerebellar activity and the thalamus during time discrimination. Developmental changes in task performance and brain activation patterns were only observed during the SRC task, with increased neural activity in the left inferior parietal gyrus and positive coupling between fronto-parietal brain regions that was only observed in the adolescents group. These results suggest that although both cognitive tasks rely on a shared neural network, distinct developmental curves of brain activation and connectivity could be observed associated with differential maturation patterns underlying cognitive development.