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1.
Neuroimage Clin ; 27: 102268, 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32361414

RESUMO

Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32272482

RESUMO

Transgender individuals (TIs) show brain-structural alterations that differ from their biological sex as well as their perceived gender. To substantiate evidence that the brain structure of TIs differs from male and female, we use a combined multivariate and univariate approach. Gray matter segments resulting from voxel-based morphometry preprocessing of N = 1753 cisgender (CG) healthy participants were used to train (N = 1402) and validate (20% holdout N = 351) a support-vector machine classifying the biological sex. As a second validation, we classified N = 1104 patients with depression. A third validation was performed using the matched CG sample of the transgender women (TW) application sample. Subsequently, the classifier was applied to N = 26 TW. Finally, we compared brain volumes of CG-men, women, and TW-pre/post treatment cross-sex hormone treatment (CHT) in a univariate analysis controlling for sexual orientation, age, and total brain volume. The application of our biological sex classifier to the transgender sample resulted in a significantly lower true positive rate (TPR-male = 56.0%). The TPR did not differ between CG-individuals with (TPR-male = 86.9%) and without depression (TPR-male = 88.5%). The univariate analysis of the transgender application-sample revealed that TW-pre/post treatment show brain-structural differences from CG-women and CG-men in the putamen and insula, as well as the whole-brain analysis. Our results support the hypothesis that brain structure in TW differs from brain structure of their biological sex (male) as well as their perceived gender (female). This finding substantiates evidence that TIs show specific brain-structural alterations leading to a different pattern of brain structure than CG-individuals.

3.
World J Biol Psychiatry ; : 1-15, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32306867

RESUMO

Objectives: Brain morphology and its relation to endocrine parameters were examined, in order to determine the link of these parameters to treatment outcome to psychopharmacological treatment in depressed patients.Methods: We examined the potentially predictive value of Magnetic Resonance Imaging (MRI) parameters related to mineralocorticoid receptor (MR) function on the treatment outcome of depression. 16 inpatients with a major depressive episode (MDE) were studied at baseline and 14 of them approximately six weeks later. Physiological biomarkers and 3-T-structural MRI based volume measures, using FreeSurfer 6.0 software, were determined.Results: Non-responders (<50% reduction of HAMD-21; n = 6) had a significantly smaller volume of the right anterior cingulate cortex, a significantly larger ventricle to brain ratio (VBR) and third ventricle volume, and smaller volumes of the central and central-anterior corpus callosum (CC) in comparison to responders (n = 7; all p ≤ 0.05). Correlational analysis (Spearman) demonstrated that larger ventricle volume was correlated to a worse treatment outcome, higher body mass index (BMI) and smaller CC segment volume, whereas the total CC volume was negatively correlated to the saliva aldosterone/cortisol concentration ratio (AC-ratio).Conclusion: Large ventricular volume may be a predictive marker for worse treatment response to standard antidepressant treatment, potentially via compression of white matter structures. A mediating role of the previously identified markers BMI and the AC-ratio, is suggested.

4.
Transl Psychiatry ; 10(1): 110, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317621

RESUMO

Extinction learning is suggested to be a central mechanism during exposure-based cognitive behavioral psychotherapy. A positive association between the patients' pretreatment extinction learning performance and treatment outcome would corroborate the hypothesis. Indeed, there is first correlational evidence between reduced extinction learning and therapy efficacy. However, the results of these association studies may be hampered by extinction-training protocols that do not match treatment procedures. Therefore, we developed an extinction-training protocol highly tailored to the procedure of exposure therapy and tested it in two samples of 46 subjects in total. By using instructed fear acquisition training, including a consolidation period overnight, we wanted to ensure that the conditioned fear response was well established prior to extinction training, which is the case in patients with anxiety disorders prior to treatment. Moreover, the extinction learning process was analyzed on multiple response levels, comprising unconditioned stimulus (US) expectancy ratings, autonomic responses, defensive brain stem reflexes, and neural activation using functional magnetic resonance imaging. Using this protocol, we found robust fear conditioning and slow-speed extinction learning. We also observed within-group heterogeneity in extinction learning, albeit a stable fear response at the beginning of the extinction training. Finally, we found discordance between different response systems, suggesting that multiple processes are involved in extinction learning. The paradigm presented here might help to ameliorate the association between extinction learning performance assessed in the laboratory and therapy outcomes and thus facilitate translational science in anxiety disorders.

5.
Schizophr Res ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32192794

RESUMO

BACKGROUND: There is an ongoing discussion about which neurobiological correlates or symptoms separate the major psychoses (i.e. Major Depressive Disorder MDD, Bipolar Disorder BD, and Schizophrenia SZ). Psychopathological factor analyses within one of these disorders have resulted in models including one to five factors. Factor analyses across the major psychoses using a comprehensive set of psychopathological scales in the same patients are lacking. It is further unclear, whether hierarchical or unitarian models better summarize phenomena. METHOD: Patients (n = 1182) who met DSM-IV criteria for MDD, BD, SZ or schizoaffective disorder were assessed with the SANS, SAPS, HAMA, HAM-D, and YMRS. The sample was split into two and analyzed using explorative and confirmatory factor analyses to extract psychopathological factors independent of diagnosis. RESULTS: In the exploratory analysis of sample 1 (n = 593) we found 5 factors. The confirmatory analysis using sample 2 (n = 589) confirmed the 5-factor model (χ2 = 1287.842, df = 571, p < .0001: CFI = 0.932; RMSEA = 0.033). The 5-factors were depression, negative syndrome, positive formal thought disorder, paranoid-hallucinatory syndrome, and increased appetite. Increased appetite was not related to medication. None of the factors was specific for one diagnosis. Second order factor analysis revealed two higher order factors: negative/affective (I) and positive symptoms (II). CONCLUSION: This is the first study delineating psychopathological factors in a large group of patients across the spectrum of affective and psychotic disorders. In future neurobiological studies, we should consider transdiagnostic syndromes besides the traditional diagnoses.

6.
Hum Brain Mapp ; 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32198905

RESUMO

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = -0.164 to -0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = -0.173 to -0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.

7.
Cortex ; 127: 17-28, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32155474

RESUMO

The distinction between different facial emotions is crucial for interpersonal communication. Shared neural circuits for facial emotion production and perception are considered to facilitate the ability to understand other's emotional state via mirror neuron mechanisms. Little is known about how diverse emotions differentially activate the Mirror Neuron System (MNS) during facial expression processing. In a functional magnetic resonance imaging (fMRI) task, 178 healthy subjects perceived and produced emotional (happy vs angry) and non-emotional (lip-protrusion vs no movement) facial expressions. Dynamic facial expressions were displayed as 5 sec video clips. We identified three overlapping networks of neural activation for happy, angry, and non-emotional (lip-protrusion) facial expression production and perception. Importantly, this overlap was largely due to the common motor component of facial expressions. However, for happy facial expressions, we found specific MNS activation in the right temporal pole. For angry facial expressions we found such activation in the left inferior frontal gyrus, pars orbitalis, and the cerebellum (lobules VII and VIII). We extend knowledge on mirror neuron mechanisms as our results provide evidence for emotion specific shared neural activation for the production and perception of facial emotions. This emotion specific representation of other's emotion in one's own neural production system might facilitate understanding of other's mental or emotional states.

8.
BMC Psychiatry ; 20(1): 59, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041577

RESUMO

BACKGROUND: Cognitive models of psychosis postulate an important role of Theory of mind (ToM) in the formation and maintenance of delusions, but research on this plausible conjecture has gathered conflicting findings. In addition, it is still an open question whether problems in emotion recognition (ER) are associated with delusions. We examined the association of problems in ToM and ER with different aspects of delusions in a large sample of patients with psychosis enrolled in a therapy trial. This also enabled us to explore the possible impact of ToM and ER on one part of patients' social life: the quality of their therapeutic relationship. METHODS: Patients with psychotic disorders and delusions and/or hallucinations (n = 185) and healthy controls (n = 48) completed a ToM picture sequencing task and an ER task. Subsequently, patients were enrolled in a randomized-controlled Cognitive Behavior Therapy (CBT) trial (ISRCTN29242879). Patients and therapists rated the quality of the therapeutic relationship during the first five sessions of therapy. RESULTS: In comparison to controls, patients were impaired in both ToM and ER. Patients with deficits in ER experienced more severe delusional distress, whereas ToM problems were not related to delusions. In addition, deficits in ER predicted a less favorable therapeutic relationship and interactional problems viewed by the therapist. Impaired ER also moderated (increased) the negative influence of delusions on the therapeutic relationship and interactional difficulties viewed by the therapist. CONCLUSIONS: Cognitive models on the formation and maintenance of delusions should consider ER as a potential candidate that might be related to the formation and maintenance of delusional distress, whereas problems in ToM might not be directly related to delusions and secondary dimensions of delusions. In addition, problems in ER in patients with psychosis might have an impact on the quality of the therapeutic relationship and patients with problems in ER are more likely to be viewed as problematic by their therapists. Nevertheless, training ER might be a way to improve the quality of the therapeutic relationship and potentially the effectiveness of CBT or other interventions for patients with psychosis.

9.
Cortex ; 126: 153-172, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32078820

RESUMO

Social group membership modulates the neural processing of emotional facial expressions, which, in turn, recruits part of the neural production system. However, little is known about how mixed - and potentially conflicting - social identity cues affect this mechanism. In this study, we tested the hypothesis that incongruent cues of two group memberships (ethnic and experimentally created minimal groups) elicit conflict processing for neutral and, in particular, angry facial expressions. We further expected this interaction of ethnic group, minimal group and emotion to also modulate activation in an emotional production-perception network. Twenty-two healthy German subjects saw dynamic angry and neutral facial expressions, presented in short video clips during functional MRI scanning. All depicted actors belonged to an ethnic in- or outgroup (German or Turkish descent) as well as an ad hoc experimentally created minimal in- or outgroup. Additionally, subjects produced angry or neutral expressions themselves. The whole-brain interaction of ethnic group, minimal group and emotion revealed activity in the right parietal lobule and left cerebellum. Both showed strongest activation for angry faces with conflicting group memberships (e.g., 'ethnic outgroup/minimal ingroup'). In addition, a sub-region of the left cerebellum cluster was also activated for both perceiving and producing angry versus neutral expressions. These results suggest that incongruent group members displaying angry facial expressions elicit conflict processing. Group interaction effects in an emotional production-perception network further indicate stronger neural resonance for incongruent group members.

10.
Hum Brain Mapp ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32090439

RESUMO

Forward models can predict sensory consequences of self-action, which is reflected by less neural processing for actively than passively generated sensory inputs (BOLD suppression effect). However, it remains open whether forward models take the identity of a moving body part into account when predicting the sensory consequences of an action. In the current study, fMRI was used to investigate the neural correlates of active and passive hand movements during which participants saw either an on-line display of their own hand or someone else's hand moving in accordance with their movement. Participants had to detect delays (0-417 ms) between their movement and the displays. Analyses revealed reduced activation in sensory areas and higher delay detection thresholds for active versus passive movements. Furthermore, there was increased activation in the hippocampus, the amygdala, and the middle temporal gyrus when someone else's hand was seen. Most importantly, in posterior parietal (angular gyrus and precuneus), frontal (middle, superior, and medial frontal gyrus), and temporal (middle temporal gyrus) regions, suppression for actively versus passively generated feedback was stronger when participants were viewing their own compared to someone else's hand. Our results suggest that forward models can take hand identity into account when predicting sensory action consequences.

11.
Schizophr Bull ; 46(2): 432-441, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31424555

RESUMO

In the last 2 decades, several neuroimaging studies investigated brain abnormalities associated with the early stages of psychosis in the hope that these could aid the prediction of onset and clinical outcome. Despite advancements in the field, neuroimaging has yet to deliver. This is in part explained by the use of univariate analytical techniques, small samples and lack of statistical power, lack of external validation of potential biomarkers, and lack of integration of nonimaging measures (eg, genetic, clinical, cognitive data). PSYSCAN is an international, longitudinal, multicenter study on the early stages of psychosis which uses machine learning techniques to analyze imaging, clinical, cognitive, and biological data with the aim of facilitating the prediction of psychosis onset and outcome. In this article, we provide an overview of the PSYSCAN protocol and we discuss benefits and methodological challenges of large multicenter studies that employ neuroimaging measures.

12.
Nervenarzt ; 91(1): 2-9, 2020 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-31559478

RESUMO

Cognitive disorders in schizophrenia are highly correlated with the psychosocial level (e.g. relationships, quality of life and work). It has been shown that healthy relatives and people at ultrahigh risk also display cognitive dysfunctions albeit to a lesser degree. The cognitive impairment increases simultaneously with an acute phase and then reverts back to baseline levels. At the psychopathological level, negative symptoms and the disorganization syndrome show the strongest associations with cognitive deficits, whereby the extent of manifestation of deficits increases with increasing symptomatology. Cognitive remediation can improve the cognitive performance through training with small to moderate effects. With respect to drug therapy there is currently no drug with a positive effect on cognitive disorders.


Assuntos
Transtornos Cognitivos , Esquizofrenia , Cognição , Transtornos Cognitivos/complicações , Humanos , Testes Neuropsicológicos , Qualidade de Vida , Esquizofrenia/complicações , Psicologia do Esquizofrênico
13.
Neuroimage ; 206: 116309, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669300

RESUMO

Tool use is one of the most remarkable skills of the human species, enabling complex interactions with the environment. To establish such interactions, we predict the sensory consequences of our actions based on a copy of the motor command (efference copy), leading to an attenuated perception and neural suppression of the sensory input. Here, we investigated whether and how tools can be incorporated into these predictions. We hypothesized that similar predictive mechanisms are used for both hand and tool use actions, but that additional resources are needed to integrate the tool. During fMRI data acquisition, 19 healthy participants used either their right hand or a tool to hold the handle of a movement device. To manipulate the effect of the efference copy, the handle was moved either actively by participants or passively by the movement device. The sensory outcome, consisting of a real-time video of the hand or tool movement shown on a screen, was presented with varying delays (0-417 ms). Participants reported their perception of such delays. The processing of hand and tool movements yielded largely similar results when comparing active against passive conditions: Active movements were in both cases associated with worse delay detection performances. Moreover, during both hand and tool use actions, active movements led to a downregulation of sensory (somatosensory, visual) areas as well as the right cerebellum and right posterior parietal cortex, as assessed by a conjunction analysis. By contrast, an interaction analysis indicated differential processing of active vs. passive movements in hand vs. tool conditions in the left postcentral gyrus, right middle temporal gyrus (MTG), and bilateral caudate nuclei. Our findings provide behavioral and neural support that hand and tool actions share similar mechanisms for sensory predictions. We propose that the MTG and (sensori)motor areas (postcentral gyrus, caudate nuclei) contribute to these predictions by optimizing them to the physics of the end effector (hand or tool). Collectively, these results suggest that the brain dynamically adjusts sensorimotor predictive models to anticipate the dynamics of the end effector, be it a hand or a tool.

14.
Am J Psychiatry ; 177(3): 254-264, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31838872

RESUMO

OBJECTIVE: Cognitive-behavioral therapy (CBT) has been hypothesized to act by reducing the pathologically enhanced semantic, anxiety-related associations of patients with panic disorder. This study investigated the effects of CBT on the behavioral and neural correlates of the panic-related semantic network in patients with panic disorder. METHODS: An automatic semantic priming paradigm specifically tailored for panic disorder, in which panic symptoms (e.g., "dizziness") were primed by panic triggers (e.g., "elevator") compared with neutral words (e.g., "bottle"), was performed during functional MRI scanning with 118 patients with panic disorder (compared with 150 healthy control subjects) before and 42 patients (compared with 52 healthy control subjects) after an exposure-based CBT. Neural correlates were investigated by comparing 103 pairs of matched patients and control subjects at the baseline (for patients) or T1 (for control subjects) assessment and 39 pairs at the posttreatment or T2 assessment. RESULTS: At baseline or T1, patients rated panic-trigger/panic-symptom word pairs with higher relatedness and higher negative valence compared with healthy control subjects. Patients made faster lexical decisions to the panic-symptom words when they were preceded by panic-trigger words. This panic-priming effect in patients (compared with control subjects) was reflected in suppressed neural activation in the left and right temporal cortices and insulae and enhanced activation in the posterior and anterior cingulate cortices. After CBT, significant clinical improvements in the patient group were observed along with a reduction in relatedness and negative valence rating and attenuation of neural activation in the anterior cingulate cortex for processing of panic-trigger/panic-symptom word pairs. CONCLUSIONS: The findings support a biased semantic network in panic disorder, which is normalized after CBT. Attenuation of anterior cingulate cortex activation for processing of panic-related associations provides a potential mechanism for future therapeutic interventions.

16.
J Vis ; 19(14): 4, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31826249

RESUMO

Sensory consequences of self-generated as opposed to externally generated movements are perceived as less intense and lead to less neural activity in corresponding sensory cortices, presumably due to predictive mechanisms. Self-generated sensory inputs have been mostly studied in a single modality, using abstract feedback, with control conditions not differentiating efferent from reafferent feedback. Here we investigated the neural processing of (a) naturalistic action-feedback associations of (b) self-generated versus externally generated movements, and (c) how an additional (auditory) modality influences neural processing and detection of delays. Participants executed wrist movements using a passive movement device (PMD) as they watched their movements in real time or with variable delays (0-417 ms). The task was to judge whether there was a delay between the movement and its visual feedback. In the externally generated condition, movements were induced by the PMD to disentangle efferent from reafferent feedback. Half of the trials involved auditory beeps coupled to the onset of the visual feedback. We found reduced BOLD activity in visual, auditory, and somatosensory areas during self-generated compared with externally generated movements in unimodal and bimodal conditions. Anterior and posterior cerebellar areas were engaged for trials in which action-feedback delays were detected for self-generated movements. Specifically, the left cerebellar lobule IX was functionally connected with the right superior occipital gyrus. The results indicate efference copy-based predictive mechanisms specific to self-generated movements, leading to BOLD suppression in sensory areas. In addition, our results support the cerebellum's role in the detection of temporal prediction errors during our actions and their consequences.

17.
Mol Psychiatry ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31758093

RESUMO

Major depressive disorder (MDD) is associated to affected brain wiring. Little is known whether these changes are stable over time and hence might represent a biological predisposition, or whether these are state markers of current disease severity and recovery after a depressive episode. Human white matter network ("connectome") analysis via network science is a suitable tool to investigate the association between affected brain connectivity and MDD. This study examines structural connectome topology in 464 MDD patients (mean age: 36.6 years) and 432 healthy controls (35.6 years). MDD patients were stratified categorially by current disease status (acute vs. partial remission vs. full remission) based on DSM-IV criteria. Current symptom severity was assessed continuously via the Hamilton Depression Rating Scale (HAMD). Connectome matrices were created via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging. Global tract-based metrics were not found to show significant differences between disease status groups, suggesting conserved global brain connectivity in MDD. In contrast, reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with HAMD, an effect remaining when correcting for lifetime disease severity. Therefore, our findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode.

18.
Neuroimage Clin ; 24: 102029, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31734525

RESUMO

INTRODUCTION: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural "fear network". We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli. METHOD: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific "Westphal-Paradigm". It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety. RESULTS: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC). DISCUSSION: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.

19.
Mol Psychiatry ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712720

RESUMO

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

20.
Psychol Med ; : 1-12, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31615588

RESUMO

BACKGROUND: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. METHOD: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. RESULTS: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. CONCLUSION: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

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