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1.
J Neural Transm (Vienna) ; 127(11): 1527-1537, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32468273

RESUMO

While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation-DNA methyltransferases (DNMTs)-has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.

2.
Br J Psychiatry ; 217(5): 645-650, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32321595

RESUMO

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.

3.
Pharmacopsychiatry ; 53(2): 60-64, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31958850

RESUMO

INTRODUCTION: Drug-induced liver injury (DILI) is the 4th most common cause of liver damage in Western countries and can be caused by antidepressants. METHODS: Against the background of increasing antidepressant prescriptions and increasing use of polypharmacy, we analyzed administered antidepressants and other pharmacological substances, liver toxicity, comorbid somatic secondary diseases together with the occurrence of DILI in a patient population of 6 centers throughout Germany. RESULTS: The majority of the enrolled 329 patients received polypharmacological treatment in an inpatient setting. During antidepressant treatment 5.1% of the patients had elevated serum transaminase levels, whereby exactly and not more than 1 criterion proposed to be indicative for DILI, was fulfilled by 3 patients (0.9%). DISCUSSION: During patient characterization it becomes clear that a sensitization for relevant risk constellations causing liver injury in MDD patients is relevant to prevent further serious adverse events.

4.
World J Biol Psychiatry ; : 1-7, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31852378

RESUMO

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.

5.
Psychoneuroendocrinology ; 110: 104433, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31525566

RESUMO

Copeptin, the C-terminal part of the hypothalamic arginine vaspopressin (AVP) precursor, closely mirrors the production of AVP and was proposed as an easily measured novel marker of the individual stress level in man. First data in male volunteers proposed copeptin as a potential endocrine surrogate marker of cholecystokinin-tetrapeptide (CCK-4)-induced panic. We tried to replicate these pilot data and to extend them to the other sex. 46 healthy human subjects (29 men, 17 women) were given an intravenous bolus of 50 µg CCK-4. Basal and stimulated plasma copeptin was measured and panic symptoms were assessed using the Acute Panic Inventory (API). Basal copeptin was significantly lower in women vs. men, while men showed a significantly higher CCK-4-induced increase of copeptin. In contrast, female subjects displayed a signifcantly higher increase of API ratings by CCK-4. No significant correlations of panic symptoms and copeptin release induced by CCK-4 could be found, neither in man, nor in women, nor in the total sample. A sexual dimorphism in copeptin secretion and in panic response was demonstrated. Prior unexpected findings of copeptin release as an objective read-out of panic could not be replicated. The role of the vasopressinergic system in panic anxiety needs further study in panic patients and in healthy man, using also other panic provocation paradigms.


Assuntos
Glicopeptídeos/sangue , Transtorno de Pânico/induzido quimicamente , Transtorno de Pânico/diagnóstico , Pânico/efeitos dos fármacos , Caracteres Sexuais , Tetragastrina/efeitos adversos , Adaptação Psicológica/efeitos dos fármacos , Adulto , Biomarcadores/sangue , Feminino , Glicopeptídeos/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Transtorno de Pânico/sangue , Via Secretória/efeitos dos fármacos , Adulto Jovem
6.
Int J Mol Sci ; 20(14)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319604

RESUMO

Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell phenotype and function associated with susceptibility and resilience to depression remain largely unknown. Here, we characterized splenic T cells in susceptible and resilient mice after 10 days of social defeat stress (SDS). We found equally decreased T cell frequencies and comparably altered expression levels of genes associated with T helper (Th) cell function in resilient and susceptible mice. Interleukin (IL)-17 producing CD4+ and CD8+ T cell numbers in the spleen were significantly increased in susceptible mice. These animals further exhibited significantly reduced numbers of regulatory T cells (Treg) and decreased gene expression levels of TGF-ß. Mice with enhanced Th17 differentiation induced by conditional deletion of PPARγ in CD4+ cells (CD4-PPARγKO), an inhibitor of Th17 development, were equally susceptible to SDS when compared to CD4-PPARγWT controls. These data indicate that enhanced Th17 differentiation alone does not alter stress vulnerability. Thus, SDS promotes Th17 cell and suppresses Treg cell differentiation predominantly in susceptible mice with yet unknown effects in immune responses after stress exposure.


Assuntos
Diferenciação Celular/imunologia , Estresse Psicológico/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Suscetibilidade a Doenças , Masculino , Camundongos , Estresse Psicológico/patologia , Linfócitos T Reguladores/patologia , Células Th17/patologia
7.
Eur Neuropsychopharmacol ; 29(10): 1161-1167, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31353282

RESUMO

Panic disorder (PD) is frequently comorbid with major depressive disorder (MDD), which has been associated with impaired treatment response and recovery rates. Alterations in the serotonergic system may play a crucial role in the pathogenesis of PD and MDD and might constitute a shared biological trunk of both disorders. Epigenetic patterns such as hypermethylation of the serotonin transporter gene (SLC6A4) have been associated with various mental disorders including MDD, but, to date, no association with PD has been reported. In the present study, SLC6A4 promoter methylation was investigated in two independent samples of PD patients in a case-control design (sample 1: N = 120; sample 2: N = 118), while - given the reported high comorbidity of both disorders - taking into account the effect of comorbid MDD. The functional relevance of altered SLC6A4 promoter methylation was investigated by means of luciferase-based reporter gene assays. SLC6A4 promoter hypermethylation in PD patients relative to healthy controls was driven by comorbid diagnosis of MDD (p = 9 × 10-6), whereas no altered methylation levels were observed in patients without comorbid MDD. This held true not only in comparison to healthy controls, but also in direct comparison between PD patients with and without comorbid MDD (p = .009). Functional analyses revealed increased methylation of the investigated region to confer decreased reporter gene activity. The present results suggest functionally relevant SLC6A4 promoter hypermethylation as a possibly specific epigenetic marker of MDD, but not of PD itself, and thus might constitute a selective biomarker informing differential diagnosis based on individual epigenetic profiles.


Assuntos
Metilação de DNA , Transtorno Depressivo Maior/genética , Epigênese Genética , Transtorno de Pânico/genética , Regiões Promotoras Genéticas/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Masculino , Adulto Jovem
8.
Neuroimage ; 191: 367-379, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30716460

RESUMO

Hemispheric asymmetries play an important role in multiple cerebral functions. Asymmetries in prefrontal cortex (PFC) function have been suggested to regulate emotional processing in that right-hemispheric dominance biases towards negative affect, whereas left PFC dominance favors positive affect. This study used transcranial magnetic stimulation to test the causal role of prefrontal asymmetries in the processing of emotional stimuli. To experimentally induce hemispheric asymmetries, 21 healthy volunteers underwent two separate sessions of inhibitory continuous theta burst stimulation (cTBS) to the left versus right dorsolateral prefrontal cortex. Each stimulation was followed by magnetoencephalographic (MEG) recordings of event-related fields elicited by visually presented emotional words in a silent reading task and a subsequent behavioral emotion categorization task. The asymmetry manipulation influenced valence processing of words in early, mid-latency and late time intervals in right occipitotemporal and parietal brain regions. Left-sided cTBS (inducing right-hemispheric dominance) consistently resulted in enhanced brain responses to negative words, while right-sided cTBS (inducing left-hemispheric dominance) enhanced responses to positive words. On a behavioral level, right-hemispheric dominance resulted in more categorization matches of negative compared to positive words, while left-hemispheric dominance resulted in reverse effects. These results provide direct evidence that bottom-up valence processing is influenced by prefrontal hemispheric asymmetry.


Assuntos
Emoções/fisiologia , Lateralidade Funcional/fisiologia , Córtex Pré-Frontal/fisiologia , Adulto , Feminino , Humanos , Magnetoencefalografia , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Estimulação Magnética Transcraniana , Adulto Jovem
9.
Transl Psychiatry ; 9(1): 75, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718541

RESUMO

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.


Assuntos
Agorafobia , Aprendizagem da Esquiva/fisiologia , Cérebro/fisiopatologia , Terapia Cognitivo-Comportamental , Medo/fisiologia , Receptores de Orexina/genética , Avaliação de Resultados em Cuidados de Saúde , Transtorno de Pânico , Adulto , Agorafobia/genética , Agorafobia/fisiopatologia , Agorafobia/terapia , Estudos de Casos e Controles , Cérebro/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/genética , Transtorno de Pânico/fisiopatologia , Transtorno de Pânico/terapia , Fenótipo , Adulto Jovem
10.
Nervenarzt ; 90(7): 715-723, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-30715554

RESUMO

BACKGROUND: Virtual reality (VR) has been investigated as a medium for exposure therapy of anxiety disorders for 20 years. Various meta-analyses have provided convincing evidence of the therapeutic efficacy of exposure therapy in VR. OBJECTIVE: In recent years VR technology and its applications have considerably improved. Therefore, the current state of the art of VR exposure therapy is presented. MATERIAL AND METHODS: This article provides a narrative review of current research on VR exposure therapy for anxiety disorders and major directions of development in this area. RESULTS: After an almost exclusive focus on specific phobias in the early days, research on more complex anxiety disorders (particularly on social anxiety disorder) is increasing. In addition, VR has become established as an experimental method to probe psychopathological processes and to elucidate the mechanism of action of (VR) exposure therapy. CONCLUSION: There is still a need for more research into VR exposure therapy, especially in complex anxiety disorders (e. g. panic disorder, agoraphobia and social anxiety disorder) and trauma-related disorders. Furthermore, VR has become established as a research tool. The rapid technological development gives reason to expect a continuing increase in VR research, in clinical as well as basic research.


Assuntos
Transtornos de Ansiedade , Terapia de Exposição à Realidade Virtual , Transtornos de Ansiedade/terapia , Humanos , Transtorno de Pânico/terapia , Transtornos Fóbicos/terapia , Terapia de Exposição à Realidade Virtual/normas , Terapia de Exposição à Realidade Virtual/tendências
11.
Mol Psychiatry ; 24(10): 1549-1564, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-29795411

RESUMO

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as 'umbrella mediator' of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention.


Assuntos
Agressão/psicologia , Violência/psicologia , Adolescente , Adulto , Experiências Adversas da Infância , Epigênese Genética/genética , Exposição à Violência/psicologia , Feminino , Histona Desacetilase 1/genética , Humanos , Masculino , Razão de Chances , Fatores de Risco , Esquizofrenia/epidemiologia , Esquizofrenia/genética
12.
Brain Stimul ; 12(2): 335-343, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30554869

RESUMO

BACKGROUND: Electroconvulsive therapy (ECT) and depression have been associated with brain volume changes, especially in the hippocampus and the amygdala. METHODS: In this retrospective study we collected data from individual pre-post ECT whole brain magnetic resonance imaging scans of depressed patients from six German university hospitals. Gray matter volume (GMV) changes were quantified via voxel-based morphometry in a total sample of 92 patients with major depressive episodes (MDE). Additionally, 43 healthy controls were scanned twice within a similar time interval. RESULTS: Most prominently longitudinal GMV increases occurred in temporal lobe regions. Within specific region of interests we detected significant increases of GMV in the hippocampus and the amygdala. These results were more pronounced in the right hemisphere. Decreases in GMV were not observed. GMV changes did not correlate with psychopathology, age, gender or number of ECT sessions. We ruled out white matter reductions as a possible indirect cause of the detected GMV increase. CONCLUSION: The present findings support the notion of hippocampus and amygdala modulation following an acute ECT series in patients with MDE. These results corroborate the hypothesis that ECT enables primarily unspecific and regionally dependent neuroplasticity effects to the brain.


Assuntos
Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia/métodos , Substância Cinzenta/diagnóstico por imagem , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Mapeamento Encefálico , Transtorno Depressivo Maior/fisiopatologia , Eletroconvulsoterapia/efeitos adversos , Feminino , Substância Cinzenta/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal
14.
Fortschr Neurol Psychiatr ; 86(6): 348-355, 2018 06.
Artigo em Alemão | MEDLINE | ID: mdl-29954017

RESUMO

Neuropsychological assessment should be an integral component of clinical psychiatric diagnostics. Yet, the commonly used tests have not been investigated adequately for this population so far. The current study evaluated a clinically approved neuropsychological test battery by analyzing data on 226 mentally ill patients using factor and regression analyses. The extraction of three factors (Speed, Memory, and Executive Functions) proved to be adequate as the tests could be allocated properly. Regression analysis revealed an economical basis assessment consisting of three tests (TAP Alertness, VLMT, and Matrices Test). Based on acceptance, economy, and factorial structure aspects, we recommend the investigated test battery for neuropsychological assessment of psychiatric and psychosomatic patients.


Assuntos
Transtornos Mentais/psicologia , Testes Neuropsicológicos , Transtornos Psicofisiológicos/psicologia , Adolescente , Adulto , Idoso , Função Executiva , Análise Fatorial , Feminino , Humanos , Masculino , Memória , Transtornos Mentais/diagnóstico , Pessoa de Meia-Idade , Transtornos Psicofisiológicos/diagnóstico , Tempo de Reação , Análise de Regressão , Reprodutibilidade dos Testes , Adulto Jovem
15.
Artigo em Inglês | MEDLINE | ID: mdl-29628065

RESUMO

BACKGROUND: Excitatory repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (dlPFC) is approved by the U.S. Food and Drug Administration for the treatment of adult patients with treatment-resistant major depressive disorder (MDD). This stimulation is supposed to restore excitability of prefrontal cortex regions that exhibit diminished regulation of emotion-generative systems in MDD. Based on the valence lateralization hypothesis, inhibitory rTMS of the right dlPFC has also been applied in MDD. This approach has proved to be effective, although meta-analyses of emotional perception and affective regulation in healthy control subjects and patients with depression do not support functional asymmetries within dlPFC regions. METHODS: To shed more light on this discrepancy, the effects of excitatory and inhibitory rTMS of the right dlPFC on visual emotional perception were compared in two groups of 41 healthy participants overall. Before and after rTMS stimulation, participants viewed fearful and neutral faces while whole-head magnetoencephalography was recorded and supplemented by behavioral tests. RESULTS: Visual sensory processing of fearful facial expressions, relative to neutral facial expressions, was reduced after excitatory stimulation and was increased after inhibitory stimulation within right occipital and right temporal regions. Correspondingly, after excitatory rTMS compared with inhibitory rTMS, participants displayed relatively reduced reaction times in an emotion discrimination task and showed reduced emotional arousal. CONCLUSIONS: These results support the hypothesis that excitatory rTMS compared with inhibitory rTMS of the right dlPFC strengthens top-down control of aversive stimuli in healthy control subjects, which should encourage more research on mechanisms of excitatory/inhibitory dlPFC-rTMS protocols in general and on neuromodulatory treatment of MDD.


Assuntos
Transtorno Depressivo Maior/fisiopatologia , Emoções/fisiologia , Córtex Pré-Frontal/fisiologia , Percepção Visual/fisiologia , Adulto , Expressão Facial , Medo/fisiologia , Feminino , Humanos , Masculino , Córtex Pré-Frontal/fisiopatologia , Estimulação Magnética Transcraniana/métodos
16.
Neuroimage Clin ; 16: 668-677, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29085773

RESUMO

BACKGROUND: A relevant proportion of patients with panic disorder (PD) does not improve even though they receive state of the art treatment for anxiety disorders such as cognitive-behavioural therapy (CBT). At the same time, it is known, that from a neurobiological point of view, PD patients are often characterised by prefrontal hypoactivation. Intermittent Theta Burst Stimulation (iTBS) is a non-invasive type of neurostimulation which can modulate cortical activity and thus has the potential to normalise prefrontal hypoactivity found in PD. We therefore aimed at investigating the effects of iTBS as an innovative add-on to CBT in the treatment for PD. METHODS: In this double-blind, bicentric study, 44 PD patients, randomised to sham or verum stimulation, received 15 sessions of iTBS over the left prefrontal cortex (PFC) in addition to 9 weeks of group CBT. Cortical activity during a cognitive as well as an emotional (Emotional Stroop) paradigm was assessed both at baseline and post-iTBS treatment using functional near-infrared spectroscopy (fNIRS) and compared to healthy controls. RESULTS: In this manuscript we only report the results of the emotional paradigm; for the results of the cognitive paradigm please refer to Deppermann et al. (2014). During the Emotional Stroop test, PD patients showed significantly reduced activation to panic-related compared to neutral stimuli for the left PFC at baseline. Bilateral prefrontal activation for panic-related stimuli significantly increased after verum iTBS only. Clinical ratings significantly improved during CBT and remained stable at follow-up. However, no clinical differences between the verum- and sham-stimulated group were identified, except for a more stable reduction of agoraphobic avoidance during follow-up in the verum iTBS group. LIMITATIONS: Limitations include insufficient blinding, the missing control for possible state-dependent iTBS effects, and the timing of iTBS application during CBT. CONCLUSION: Prefrontal hypoactivity in PD patients was normalised by add-on iTBS. Clinical improvement of anxiety symptoms was not affected by iTBS.


Assuntos
Agorafobia/terapia , Terapia Cognitivo-Comportamental , Transtorno de Pânico/terapia , Córtex Pré-Frontal/fisiopatologia , Estimulação Magnética Transcraniana , Adulto , Agorafobia/diagnóstico por imagem , Agorafobia/fisiopatologia , Método Duplo-Cego , Emoções/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/diagnóstico por imagem , Transtorno de Pânico/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Espectroscopia de Luz Próxima ao Infravermelho , Teste de Stroop , Resultado do Tratamento , Adulto Jovem
17.
J Psychiatry Neurosci ; 42(5): 343-352, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28606245

RESUMO

BACKGROUND: Identifying reliable trait markers of familial risk for major depressive disorder (MDD) is a challenge in translational psychiatric research. In individuals with acute MDD, dysfunctional connectivity patterns of prefrontal areas have been shown repeatedly. However, it has been unclear in which neuronal networks functional alterations in individuals at familial risk for MDD might be present and to what extent they resemble findings previously reported in those with acute MDD. METHODS: We investigated differences in blood oxygen level-dependent (BOLD) response of the medial orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) to aversive stimuli between acute MDD and familial risk for the disorder in healthy first-degree relatives of acutely depressed patients with MDD (HC-FH+), healthy age- and sex-matched controls without any family history of depression (HC-FH-), and acutely depressed patients with MDD with (MDD-FH+) and without a family history of depression (MDD-FH-) during a frequently used emotional face-matching paradigm. Analyses of task-specific network connectivity were conducted in terms of psychophysiological interactions (PPI). RESULTS: The present analysis included a total of 100 participants: 25 HC-FH+, 25 HC-FH-, 25 MDD-FH+ and 25 MDD-FH-. Patients with MDD exhibited significantly increased activation in the medial OFC to negative stimuli irrespective of familial risk status, whereas healthy participants at familial risk and patients with MDD alike showed significant hypoactivation in the DLPFC compared with healthy participants without familial risk. The PPI analyses revealed significantly enhanced task-specific coupling between the medial OFC and differing cortical areas in individuals with acute MDD and those with familial risk for the disorder. LIMITATIONS: The main limitation of our study is its cross-sectional design. CONCLUSION: Whereas hypoactivation during negative emotion processing in the DLPFC appears as a common feature in both healthy high-risk individuals and acutely depressed patients, activation patterns of the medial OFC and its underlying connectivity seem to distinguish familial risk from acute disorder.


Assuntos
Transtorno Depressivo Maior/fisiopatologia , Emoções/fisiologia , Família , Predisposição Genética para Doença , Córtex Pré-Frontal/fisiopatologia , Adulto , Mapeamento Encefálico , Circulação Cerebrovascular/fisiologia , Estudos Transversais , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/genética , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Oxigênio/sangue , Córtex Pré-Frontal/diagnóstico por imagem
18.
Eur Arch Psychiatry Clin Neurosci ; 267(8): 751-766, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28246891

RESUMO

Transcranial direct current stimulation (tDCS) has been proposed as novel treatment for major depressive disorder (MDD) based on clinical pilot studies as well as randomized controlled monocentric trials. The DepressionDC trial is a triple-blind (blinding of rater, operator and patient), randomized, placebo controlled multicenter trial investigating the efficacy and safety of prefrontal tDCS used as additive treatment in MDD patients who have not responded to selective serotonin reuptake inhibitors (SSRI). At 5 study sites, 152 patients with MDD receive a 6-weeks treatment with active tDCS (anode F3 and cathode F4, 2 mA intensity, 30 min/day) or sham tDCS add-on to a stable antidepressant medication with an SSRI. Follow-up visits are at 3 and 6 months after the last tDCS session. The primary outcome measure is the change of the Montgomery-Asberg Depression Rating Scale (MADRS) scores at week 6 post-randomisation compared to baseline. Secondary endpoints also cover other psychopathological domains, and a comprehensive safety assessment includes measures of cognition. Patients undergo optional investigations comprising genetic testing and functional magnetic resonance imaging (fMRI) of structural and functional connectivity. The study uses also an advanced tDCS technology including standard electrode positioning and recording of technical parameters (current, impedance, voltage) in every tDCS session. Aside reporting the study protocol here, we present a novel approach for monitoring technical parameters of tDCS which will allow quality control of stimulation and further analysis of the interaction between technical parameters and clinical outcome. The DepressionDC trial will hopefully answer the important clinical question whether prefrontal tDCS is a safe and effective antidepressant intervention in patients who have not sufficiently responded to SSRIs. TRIAL REGISTRY: ClinicalTrials.gov Identifier NCT0253016.


Assuntos
Transtorno Depressivo Maior/terapia , Avaliação de Processos e Resultados em Cuidados de Saúde/métodos , Córtex Pré-Frontal , Projetos de Pesquisa , Inibidores de Captação de Serotonina/farmacologia , Estimulação Transcraniana por Corrente Contínua/métodos , Adulto , Terapia Combinada , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Placebos , Inibidores de Captação de Serotonina/administração & dosagem
19.
Neuroimage Clin ; 14: 530-537, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28331799

RESUMO

Different degrees of threat predictability are thought to induce either phasic fear or sustained anxiety. Maladaptive, sustained anxious apprehension is thought to result in overgeneralization of anxiety and thereby to contribute to the development of anxiety disorders. Therefore, differences in threat predictability have been associated with pathological states of anxiety with specific phobia (SP) representing phasic fear as heightened response to predictable threat, while panic disorder (PD) is characterized by sustained anxiety (unpredictable threat) and, as a consequence, overgeneralization of fear. The present study aimed to delineate commonalities and differences in the neural substrates of the impact of threat predictability on affective processing in these two anxiety disorders. Twenty PD patients, 20 SP patients and 20 non-anxious control subjects were investigated with an adapted NPU-design (no, predictable, unpredictable threat) using whole-head magnetoencephalography (MEG). Group independent neural activity in the right dlPFC increased with decreasing threat predictability. PD patients showed a sustained hyperactivation of the vmPFC under threat and safety conditions. The magnitude of hyperactivation was inversely correlated with PDs subjective arousal and anxiety sensitivity. Both PD and SP patients revealed decreased parietal processing of affective stimuli. Findings indicate overgeneralization between threat and safety conditions and increased need for emotion regulation via the vmPFC in PD, but not SP patients. Both anxiety disorders showed decreased activation in parietal networks possibly indicating attentional avoidance of affective stimuli. Present results complement findings from fear conditioning studies and underline overgeneralization of fear, particularly in PD.


Assuntos
Mapeamento Encefálico , Transtorno de Pânico/patologia , Transtornos Fóbicos/patologia , Córtex Pré-Frontal/patologia , Adulto , Feminino , Humanos , Magnetoencefalografia , Masculino , Autorrelato , Estatística como Assunto , Adulto Jovem
20.
Eur Neuropsychopharmacol ; 27(4): 360-371, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28233670

RESUMO

The corticotropin releasing hormone receptor 1 (CRHR1) is crucially involved in the hypothalamic-pituitary-adrenal axis and thus a major regulator of the stress response. CRHR1 gene variation is associated with several mental disorders including anxiety disorders. Studies in rodents have demonstrated epigenetic regulation of CRHR1 gene expression to moderate response to stressful environment. In the present study, we investigated CRHR1 promoter methylation for the first time regarding its role in panic disorder applying a case-control approach (N=131 patients, N=131 controls). In an independent sample of healthy volunteers (N=255), CRHR1 methylation was additionally analyzed for association with the Beck Anxiety Inventory (BAI) score as a dimensional panic-related intermediate phenotype. The functional relevance of altered CRHR1 promoter methylation was investigated by means of luciferase-based reporter gene assays. In panic disorder patients, a significantly decreased CRHR1 methylation was discerned (p<0.001). Accordingly, healthy controls with high BAI scores showed significantly decreased CRHR1 methylation. Functional analyses revealed an increased gene expression in presence of unmethylated as compared to methylated pCpGl_CRHR1 reporter gene vectors. The present study identified a potential role of CRHR1 hypomethylation - conferring increased CRHR1 expression - in panic disorder and a related dimensional intermediate phenotype. This up-regulation of CRHR1 gene expression driven by de-methylation might constitute a link between the stress response and panic disorder risk.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Transtorno de Pânico/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Receptores de Hormônio Liberador da Corticotropina/genética , Adulto , Distribuição de Qui-Quadrado , Simulação por Computador , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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