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Langhammer T, Hilbert K, Adolph D, Arolt V, Bischoff S, Böhnlein J, Cwik JC, Dannlowski U, Deckert J, Domschke K, Evens R, Fydrich T, Gathmann B, Hamm AO, Heinig I, Herrmann MJ, Hollandt M, Junghoefer M, Kircher T, Koelkebeck K, Leehr EJ, Lotze M, Margraf J, Mumm JLM, Pittig A, Plag J, Richter J, Roesmann K, Ridderbusch IC, Schneider S, Schwarzmeier H, Seeger F, Siminski N, Straube T, Ströhle A, Szeska C, Wittchen HU, Wroblewski A, Yang Y, Straube B, Lueken U. Resting-state functional connectivity in anxiety disorders: a multicenter fMRI study. Mol Psychiatry 2025; 30:1548-1557. [PMID: 39367057 PMCID: PMC11919712 DOI: 10.1038/s41380-024-02768-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 08/22/2024] [Accepted: 09/25/2024] [Indexed: 10/06/2024]
Abstract
Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. It remains uncertain how much these signatures overlap across different phenotypes due to a lack of well-powered cross-disorder comparisons. We used resting-state functional magnetic resonance imaging (rsfMRI) to investigate differences in functional connectivity (FC) in a cross-disorder sample of AD patients and healthy controls (HC). Before treatment, 439 patients from two German multicenter clinical trials at eight different sites fulfilling a primary diagnosis of panic disorder and/or agoraphobia (PD/AG, N = 154), social anxiety disorder (SAD, N = 95), or specific phobia (SP, N = 190) and 105 HC underwent an 8 min rsfMRI assessment. We performed categorical and dimensional regions of interest (ROI)-to-ROI analyses focusing on connectivity between regions of the defensive system and prefrontal regulation areas. AD patients showed increased connectivity between the insula and the thalamus compared to controls. This was mainly driven by PD/AG patients who showed increased (insula/hippocampus/amygdala-thalamus) and decreased (dorsomedial prefrontal cortex/periaqueductal gray-anterior cingulate cortex) positive connectivity between subcortical and cortical areas. In contrast, SAD patients showed decreased negative connectivity exclusively in cortical areas (insula-orbitofrontal cortex), whereas no differences were found in SP patients. State anxiety associated with the scanner environment did not explain the FC between these regions. Only PD/AG patients showed pronounced connectivity changes along a widespread subcortical-cortical network, including the midbrain. Dimensional analyses yielded no significant results. The results highlighting categorical differences between ADs at a systems neuroscience level are discussed within the context of personalized neuroscience-informed treatments. PROTECT-AD's registration at NIMH Protocol Registration System: 01EE1402A and German Register of Clinical Studies: DRKS00008743. SpiderVR's registration at ClinicalTrials.gov: NCT03208400.
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Affiliation(s)
- Till Langhammer
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
| | - Kevin Hilbert
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
- Department of Psychology, HMU Health and Medical University Erfurt, Erfurt, Germany
| | - Dirk Adolph
- Mental Health Research and Treatment Center, Faculty of Psychology, Ruhr-Universität Bochum, Bochum, Germany
| | - Volker Arolt
- Institute for Translational Psychiatry, University of Münster, Münster, Germany
| | - Sophie Bischoff
- Department of Psychiatry and Psychotherapy, Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Joscha Böhnlein
- Institute for Translational Psychiatry, University of Münster, Münster, Germany
| | - Jan C Cwik
- Department of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany
- Department of Psychology and Psychotherapy, Witten/Herdecke University, Witten, Germany
| | - Udo Dannlowski
- Institute for Translational Psychiatry, University of Münster, Münster, Germany
| | - Jürgen Deckert
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Katharina Domschke
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Ricarda Evens
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Thomas Fydrich
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Bettina Gathmann
- Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany
| | - Alfons O Hamm
- Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany
| | - Ingmar Heinig
- Institute for Clinical Psychology and Psychotherapy, Technical University of Dresden, Dresden, Germany
| | - Martin J Herrmann
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany
| | - Maike Hollandt
- Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany
- Department of Clinical Psychology and Psychotherapy, University of Greifswald, Greifswald, Germany
| | - Markus Junghoefer
- Institute for Biomagnetism and Biosignalanalysis, University of Münster, Münster, Germany
- Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience, University of Münster, Münster, Germany
| | - Tilo Kircher
- Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, Philipps-Universität Marburg, Marburg, Germany
| | - Katja Koelkebeck
- LVR-University Hospital Essen, Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Duisburg, Germany
| | - Elisabeth J Leehr
- Institute for Translational Psychiatry, University of Münster, Münster, Germany
| | - Martin Lotze
- Functional Imaging Unit, Diagnostic Radiology, University Medicine Greifswald, Greifswald, Germany
| | - Jürgen Margraf
- Institute for Translational Psychiatry, University of Münster, Münster, Germany
| | - Jennifer L M Mumm
- Department of Psychiatry and Psychotherapy, Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Andre Pittig
- Translational Psychotherapy, Institute of Psychology, University of Goettingen, Göttingen, Germany
| | - Jens Plag
- Department of Medicine, Institute for Mental Health and Behavioral Medicine, HMU Health and Medical University, Potsdam, Germany
| | - Jan Richter
- Department of Experimental Psychopathology, University of Hildesheim, Hildesheim, Germany
| | - Kati Roesmann
- Institute for Biomagnetism and Biosignalanalysis, University of Münster, Münster, Germany
- Institute for Psychology, Clinical Psychology and Psychotherapy in Childhood and Adolescence, University of Osnabrueck, Osnabruck, Germany
| | - Isabelle C Ridderbusch
- Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, Philipps-Universität Marburg, Marburg, Germany
| | - Silvia Schneider
- Department of Clinical Child and Adolescent Psychology, Ruhr-University Bochum, Bochum, Germany
| | - Hanna Schwarzmeier
- Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany
| | - Fabian Seeger
- Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany
| | - Niklas Siminski
- Center for Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
| | - Thomas Straube
- Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany
- Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience, University of Münster, Münster, Germany
| | - Andreas Ströhle
- Department of Psychiatry and Psychotherapy, Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph Szeska
- Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany
- Department of Biological Psychology and Affective Science, University of Potsdam, Potsdam, Germany
| | - Hans-Ulrich Wittchen
- Institute for Clinical Psychology and Psychotherapy, Technical University of Dresden, Dresden, Germany
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU) Muenchen, Munich, Germany
| | - Adrian Wroblewski
- Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, Philipps-Universität Marburg, Marburg, Germany
| | - Yunbo Yang
- Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, Philipps-Universität Marburg, Marburg, Germany
- Department of Experimental Psychopathology, University of Hildesheim, Hildesheim, Germany
| | - Benjamin Straube
- Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, Philipps-Universität Marburg, Marburg, Germany
| | - Ulrike Lueken
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Mental Health (DZPG), partner site Berlin/Potsdam, Berlin, Germany
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Kausche FM, Carsten HP, Sobania KM, Riesel A. Fear and safety learning in anxiety- and stress-related disorders: An updated meta-analysis. Neurosci Biobehav Rev 2025; 169:105983. [PMID: 39706234 DOI: 10.1016/j.neubiorev.2024.105983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
Fear learning processes are believed to play a crucial role in the development and maintenance of anxiety and stress-related disorders. To integrate results across different studies, we conducted a systematic meta-analysis following PRISMA guidelines to examine differences in fear conditioning during fear acquisition, extinction, and extinction recall between individuals with anxiety-related or stress-related disorders and healthy participants. This analysis updates the work of Duits et al. (2015) while also refining distinctions between physiological and behavioral outcomes and examining extinction recall. Our meta-analysis encompasses 77 studies published from 1986 to 2022, involving 2052 patients with anxiety disorders, obsessive-compulsive disorder, or post-traumatic stress disorder, and 3258 healthy controls. The results indicate significant differences in fear acquisition, extinction, and recall between the two groups. Specifically, during acquisition patients exhibited heightened physiological and behavioral responses to the CS- and reported increased affect ratings for the CS+ . During extinction and extinction recall, patients continue to show heightened threat expectancy and negative affect ratings towards the CS- and increased affect ratings towards the CS+ . No differences were found in CS+ /CS- differentiation between groups. These findings imply that individuals with anxiety and stress-related disorders may exhibit amplified responses to safety cues and stronger reactions to threat cues during fear conditioning, lasting through extinction and extinction recall. These changes may lead to increased sensitivity in detecting fear and slower extinction process, resulting in more enduring anxiety responses. We discuss these results in the context of existing literature on fear and safety learning and consider potential underlying mechanisms.
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Affiliation(s)
| | | | - Kim M Sobania
- Department of Psychology, University Hamburg, Hamburg, Germany
| | - Anja Riesel
- Department of Psychology, University Hamburg, Hamburg, Germany
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Ma Y, Jiao F, Batsikadze G, Yavari F, Nitsche MA. The impact of the left inferior frontal gyrus on fear extinction: A transcranial direct current stimulation study. Brain Stimul 2024; 17:816-825. [PMID: 38997105 DOI: 10.1016/j.brs.2024.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 06/03/2024] [Accepted: 07/06/2024] [Indexed: 07/14/2024] Open
Abstract
INTRODUCTION Fear extinction is a fundamental component of exposure-based therapies for anxiety-related disorders. The renewal of fear in a different context after extinction highlights the importance of contextual factors. In this study, we aimed to investigate the causal role of the left inferior frontal gyrus (LiFG) in the context-dependency of fear extinction learning via administration of transcranial direct current stimulation (tDCS) over this area. METHODS 180 healthy subjects were assigned to 9 groups: 3 tDCS conditions (anodal, cathodal, and sham) × 3 context combinations (AAA, ABA, and ABB). The fear conditioning/extinction task was conducted over three consecutive days: acquisition, extinction learning, and extinction recall. tDCS (2 mA, 10min) was administered during the extinction learning phase over the LiFG via a 4-electrode montage. Skin conductance response (SCR) data and self-report assessments were collected. RESULTS During the extinction learning phase, groups with excitability-enhancing anodal tDCS showed a significantly higher fear response to the threat cues compared to cathodal and sham stimulation conditions, irrespective of contextual factors. This effect was stable until the extinction recall phase. Additionally, excitability-reducing cathodal tDCS caused a significant decrease of the response difference between the threat and safety cues during the extinction recall phase. The self-report assessments showed no significant differences between the conditions throughout the experiment. CONCLUSION Independent of the context, excitability enhancement of the LiFG did impair fear extinction, and led to preservation of fear memory. In contrast, excitability reduction of this area enhanced fear extinction retention. These findings imply that the LiFG plays a role in the fear extinction network, which seems to be however context-independent.
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Affiliation(s)
- Yuanbo Ma
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany; Department of Psychology, Ruhr University Bochum, Bochum, Germany
| | - Fujia Jiao
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany; Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Giorgi Batsikadze
- Department of Neurology and Center for Translational Neuro and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Hufelandstraße 55, Essen, 45147, Germany
| | - Fatemeh Yavari
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany.
| | - Michael A Nitsche
- Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany; Bielefeld University, University Hospital OWL, Protestant Hospital of Bethel Foundation, University Clinic of Psychiatry and Psychotherapy, University Clinic of Child and Adolescent Psychiatry and Psychotherapy, Bielefeld, Germany; German Center for Mental Health (DZPG), Bochum, Germany.
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Karch S, Maywald M, Schwartz C, Heil C, Neumüller J, Keeser D, Garcia S, Tschentscher N, Pogarell O, Paolini M, Voderholzer U. Neuronal correlates of intensification and acceptance of symptoms during exposure therapy in patients with obsessive-compulsive disorder. Front Psychol 2024; 15:1256046. [PMID: 38375106 PMCID: PMC10875107 DOI: 10.3389/fpsyg.2024.1256046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 01/15/2024] [Indexed: 02/21/2024] Open
Abstract
Introduction Cognitive behaviour therapy with exposure and response prevention is efficient in treating patients with obsessive-compulsive disorder (OCD). Nevertheless, it would be helpful for many patients to complement the therapeutic treatment with acceptance strategies to further increase the therapeutic benefit. The aim of the present study was to examine neurobiological responses to acceptance and intensification strategies during symptom provocation alongside the psychotherapeutic process. Method A total of 23 patients diagnosed with OCD (subtype: washing/contamination fear) was instructed to utilise either an acceptance strategy (ACS) or an intensification strategy (INS) to cope with their emotional and cognitive reactions to personalised symptom-triggering and neutral pictures. Fourteen patients participated twice: at the beginning [T1] and at the end [T2] of an inpatient multimodal treatment including cognitive behaviour therapy with response prevention to assess functional variations. Results For the contrast of T1 and T2, ACS showed increased brain activity in the left inferior frontal gyrus (IFG), left caudate body, and posterior cingulate gyrus (PCC). They also showed decreased activity in the left anterior insula. INS showed decreased activation in right lingual gyrus and right caudate body. At T2, ACS showed increased activation compared to INS in the left cerebrum: IFG, caudate nucleus, middle and superior temporal gyrus, and PCC/cuneus. For the comparison of T1 and T2, the ACS revealed increased brain activity in the left IFG, left caudate body, and right inferior parietal lobe. It showed decreased activity in the left anterior insula. The INS revealed decreased activity in right lingual gyrus and right caudate body.The psychometric questionnaires suggested that patients were able to reduce obsession, compulsion, and depression symptoms. Furthermore, patients rated the ACS as more useful for themselves compared with the INS. Conclusion The increased left IFG activity using ACS (T1 vs. T2) could be interpreted as a better inhibitory top-down process, while the increased PCC response might be due to a better reappraisal strategy after therapy. ACS seems to mobilise neuronal activations under therapy, especially in the left hemisphere. Both strategies showed reductions in emotional networks as a neuronal correlate of therapy success. Overall, ACS may be more efficient than INS, as rated by the patients and as in accordance with neurobiological findings.
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Affiliation(s)
- Susanne Karch
- Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany
| | - Maximilian Maywald
- Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany
| | | | - Clara Heil
- Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany
| | | | - Daniel Keeser
- Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany
- Department of Radiology, University Hospital LMU, Munich, Germany
| | - Sarah Garcia
- Schoen Clinic Roseneck, Prien am Chiemsee, Germany
| | - Nadja Tschentscher
- Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany
| | - Oliver Pogarell
- Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany
| | - Marco Paolini
- Department of Radiology, University Hospital LMU, Munich, Germany
| | - Ulrich Voderholzer
- Department of Psychiatry and Psychotherapy, University Hospital LMU, Munich, Germany
- Schoen Clinic Roseneck, Prien am Chiemsee, Germany
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Wang HY, Zhang L, Guan BY, Wang SY, Zhang CH, Ni MF, Miao YW, Zhang BW. Resting-state cortico-limbic functional connectivity pattern in panic disorder: Relationships with emotion regulation strategy use and symptom severity. J Psychiatr Res 2024; 169:97-104. [PMID: 38007890 DOI: 10.1016/j.jpsychires.2023.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 11/10/2023] [Accepted: 11/15/2023] [Indexed: 11/28/2023]
Abstract
Cognitive reappraisal is an effective emotion regulation strategy involving prefrontal cortex (PFC) control of the amygdala. Its aberrant functioning is closely associated with panic disorder (PD). However, the resting-state functional connectivity (rsFC) between the PFC, implicated in cognitive reappraisal, and the amygdala in PD has not been studied. Thus, this study aims to investigate the rsFC patterns and their association with cognitive reappraisal and PD. This study involved 51 participants, including 26 untreated patients with PD and 25 healthy controls (HC). We evaluated the habit of cognitive reappraisal assessment and the severity of PD using neuropsychological and clinical measures. Resting-state fMRI was utilized to evaluate the rsFC pattern between the PFC, engaged in cognitive reappraisal, and the amygdala. Mediation analysis was performed to explore the role of this rsFC in the relationship between cognitive reappraisal and PD severity. PD patients showed reduced rsFC between the PFC and the amygdala compared to HC. This weakened rsFC was associated with the severity of PD symptoms. Moreover, cognitive reappraisal was negatively correlated with PD severity, and mediation analysis indicated that the rsFC of the PFC-amygdala played a mediating role in this association. Abnormal PFC-amygdala rsFC may play a pivotal role in PD development and/or manifestation and mediate the association between cognitive reappraisal and PD severity, potentially serving as a clinical indicator for monitoring and intervention.
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Affiliation(s)
- Hai-Yang Wang
- Department of Neurology, Jining No. 1 People's Hospital, Shandong First Medical University, Jining, 272000, China
| | - Lin Zhang
- Medical Equipment Department, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Bei-Yan Guan
- Department of Neurology and Psychiatry, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Shi-Yao Wang
- Department of Neurology and Psychiatry, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Cui-Hong Zhang
- Department of Neurology, Huizhou Third People's Hospital, Guangzhou Medical University, Huizhou, 516000, China
| | - Ming-Fei Ni
- Department of Radiology, First Affiliate Hospital of Dalian Medical University, Dalian, 116011, China
| | - Yan-Wei Miao
- Department of Radiology, First Affiliate Hospital of Dalian Medical University, Dalian, 116011, China
| | - Bing-Wei Zhang
- Department of Neurology and Psychiatry, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China; Department of Psychology, Dalian Medical University, Dalian, 116044, China.
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Yan H, Han Y, Shan X, Li H, Liu F, Li P, Zhao J, Guo W. Breaking the Fear Barrier: Aberrant Activity of Fear Networks as a Prognostic Biomarker in Patients with Panic Disorder Normalized by Pharmacotherapy. Biomedicines 2023; 11:2420. [PMID: 37760861 PMCID: PMC10525800 DOI: 10.3390/biomedicines11092420] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/23/2023] [Accepted: 08/26/2023] [Indexed: 09/29/2023] Open
Abstract
Panic disorder (PD) is a prevalent type of anxiety disorder. Previous studies have reported abnormal brain activity in the fear network of patients with PD. Nonetheless, it remains uncertain whether pharmacotherapy can effectively normalize these abnormalities. This longitudinal resting-state functional magnetic resonance imaging study aimed to investigate the spontaneous neural activity in patients with PD and its changes after pharmacotherapy, with a focus on determining whether it could predict treatment response. The study included 54 drug-naive patients with PD and 54 healthy controls (HCs). Spontaneous neural activity was measured using regional homogeneity (ReHo). Additionally, support vector regression (SVR) was employed to predict treatment response from ReHo. At baseline, PD patients had aberrant ReHo in the fear network compared to HCs. After 4 weeks of paroxetine treatment (20 mg/day), a significant increase in ReHo was observed in the left fusiform gyrus, which had shown reduced ReHo before treatment. The SVR analysis showed significantly positive correlations (p < 0.0001) between the predicted and actual reduction rates of the severity of anxiety and depressive symptoms. Here, we show patients with PD had abnormal spontaneous neural activities in the fear networks. Furthermore, these abnormal spontaneous neural activities can be partially normalized by pharmacotherapy and serve as candidate predictors of treatment response. Gaining insight into the trajectories of brain activity normalization following treatment holds the potential to provide vital insights for managing PD.
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Affiliation(s)
- Haohao Yan
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (H.Y.); (Y.H.); (X.S.); (J.Z.)
| | - Yiding Han
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (H.Y.); (Y.H.); (X.S.); (J.Z.)
| | - Xiaoxiao Shan
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (H.Y.); (Y.H.); (X.S.); (J.Z.)
| | - Huabing Li
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha 410011, China;
| | - Feng Liu
- Department of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, China;
| | - Ping Li
- Department of Psychiatry, Qiqihar Medical University, Qiqihar 161006, China;
| | - Jingping Zhao
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (H.Y.); (Y.H.); (X.S.); (J.Z.)
| | - Wenbin Guo
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha 410011, China; (H.Y.); (Y.H.); (X.S.); (J.Z.)
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Maywald M, Pogarell O, Levai S, Paolini M, Tschentscher N, Rauchmann BS, Krause D, Stöcklein S, Goerigk S, Röll L, Ertl-Wagner B, Papazov B, Keeser D, Karch S, Chrobok A. Neurofunctional differences and similarities between persistent postural-perceptual dizziness and anxiety disorder. Neuroimage Clin 2023; 37:103330. [PMID: 36696807 PMCID: PMC9879992 DOI: 10.1016/j.nicl.2023.103330] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023]
Abstract
INTRODUCTION Persistent postural-perceptual dizziness (PPPD) (ICD-11) and anxiety disorders (ANX) share behavioural symptoms like anxiety, avoidance, social withdrawal, hyperarousal, or palpitation as well as neurological symptoms like vertigo, stance and gait disorders. Furthermore, previous studies have shown a bidirectional link between vestibulo-spatial and anxiety neural networks. So far, there have been no neuroimaging-studies comparing these groups. OBJECTIVES The aim of this explorative study was to investigate differences and similarities of neural correlates between these two patient groups and to compare their findings with a healthy control group. METHODS 63 participants, divided in two patient groups (ANX = 20 and PPPD = 14) and two sex and age matched healthy control groups (HC-A = 16, HC-P = 13) were included. Anxiety and dizziness related pictures were shown during fMRI-measurements in a block-design in order to induce emotional responses. All subjects filled in questionnaires regarding vertigo (VSS, VHQ), anxiety (STAI), depression (BDI-II), alexithymia (TAS), and illness-perception (IPQ). After modelling the BOLD response with a standard canonical HRF, voxel-wise t-tests between conditions (emotional-negative vs neutral stimuli) were used to generate statistical contrast maps and identify relevant brain areas (pFDR < 0.05, cluster size >30 voxels). ROI-analyses were performed for amygdala, cingulate gyrus, hippocampus, inferior frontal gyrus, insula, supramarginal gyrus and thalamus (p ≤ 0.05). RESULTS Patient groups differed from both HC groups regarding anxiety, dizziness, depression and alexithymia scores; ratings of the PPPD group and the ANX group did differ significantly only in the VSS subscale 'vertigo and related symptoms' (VSS-VER). The PPPD group showed increased neural responses in the vestibulo-spatial network, especially in the supramarginal gyrus (SMG), and superior temporal gyrus (STG), compared to ANX and HC-P group. The PPPD group showed increased neural responses compared to the HC-P group in the anxiety network including amygdala, insula, lentiform gyrus, hippocampus, inferior frontal gyrus (IFG) and brainstem. Neuronal responses were enhanced in visual structures, e.g. fusiform gyrus, middle occipital gyrus, and in the medial orbitofrontal cortex (mOFC) in healthy controls compared to patients with ANX and PPPD, and in the ANX group compared to the PPPD group. CONCLUSIONS These findings indicate that neuronal responses to emotional information in the PPPD and the ANX group are comparable in anxiety networks but not in vestibulo-spatial networks. Patients with PPPD revealed a stronger neuronal response especially in SMG and STG compared to the ANX and the HC group. These results might suggest higher sensitivity and poorer adaptation processes in the PPPD group to anxiety and dizziness related pictures. Stronger activation in visual processing areas in HC subjects might be due to less emotional and more visual processing strategies.
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Affiliation(s)
- Maximilian Maywald
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
| | - Oliver Pogarell
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Susanne Levai
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Marco Paolini
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Nadja Tschentscher
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Boris Stephan Rauchmann
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany; Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Daniela Krause
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Sophia Stöcklein
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Stephan Goerigk
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Lukas Röll
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Birgit Ertl-Wagner
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Boris Papazov
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Daniel Keeser
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany; Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Susanne Karch
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Agnieszka Chrobok
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
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8
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Craske MG, Sandman CF, Stein MB. How can neurobiology of fear extinction inform treatment? Neurosci Biobehav Rev 2022; 143:104923. [DOI: 10.1016/j.neubiorev.2022.104923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 10/08/2022] [Accepted: 10/09/2022] [Indexed: 11/06/2022]
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9
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Behavioral and neural responses during fear conditioning and extinction in a large transdiagnostic sample. Neuroimage Clin 2022; 35:103060. [PMID: 35679785 PMCID: PMC9189200 DOI: 10.1016/j.nicl.2022.103060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 04/28/2022] [Accepted: 05/21/2022] [Indexed: 11/23/2022]
Abstract
Behavioral and neural responses during Pavlovian fear learning were examined in a large sample of healthy and individuals with anxiety and depression. Latent profile models to threat were derived from behavioral and neural data. Demographic, cognitive, and psychological variables did not robustly characterize latent profiles. Neuroimaging data did not evidence functional role of amygdala in fear learning. Human fear learning recruited a distributed network of regions involved in interoceptive, cognitive, motivational, and psychomotor processes. Background Dysregulation of fear learning has been associated with psychiatric disorders that have altered positive and negative valence domain function. While amygdala-insula-prefrontal circuitry is considered important for fear learning, there have been inconsistencies in neural findings in healthy and clinical human samples. This study aimed to delineate the neural substrates and behavioral responses during fear learning in a large, transdiagnostic sample with predominantly depressive and/or anxious dysfunction. Methods Two-hundred and eighty-two individuals (52 healthy participants; 230 participants with depression and/or anxiety-related problems) from the Tulsa 1000 study, an ongoing, naturalistic longitudinal study based on a dimensional psychopathological framework, completed a Pavlovian fear learning task during functional magnetic resonance imaging. Linear mixed-effects analyses examined condition-by-time effects on brain activation (CS+, CS- across familiarization, conditioning, and extinction trials). A data-driven latent profile analysis (LPA) examined distinct patterns of behavioral and neural responses to threat across fear conditioning and extinction, while logistic regression analyses evaluated cognitive-affective predictors of latent profiles. Results Whole-brain analyses revealed a condition-by-time interaction in the anterior insula, postcentral gyrus, superior temporal gyrus, middle frontal gyrus, and cerebellum but not amygdala. The LPA identified distinct latent profiles across subjective and neural levels of measurement. Anterior insula profiles were characterized by marginal differences in age and state anxiety. Conclusions Our findings demonstrate that human fear learning recruits a distributed network of regions involved in interoceptive, cognitive, motivational, and psychomotor processes. Data-driven analyses identified distinct profiles of subjective and neural responses during fear learning that transcended clinical diagnoses, but no robust relationships to demographic or cognitive-affective variable were identified.
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10
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Liu Y, Lai CH. The alterations of degree centrality in the frontal lobe of patients with panic disorder. Int J Med Sci 2022; 19:105-111. [PMID: 34975304 PMCID: PMC8692120 DOI: 10.7150/ijms.65367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 11/02/2021] [Indexed: 01/10/2023] Open
Abstract
Objective: The brain network in panic disorder (PD) is still an intriguing issue for research. In this study, we hoped to investigate the role of DC (degree centrality) for the pathophysiology of PD, especially for the fear network. Methods: We enrolled 60 patients with PD and 60 controls in the current study. The gender and age were matched for two groups. All participants received the resting-state functional magnetic resonance imaging to survey the baseline brain activity. Then the DC values of all participants were using REST toolbox. We also compared the DC values between PD and controls. The statistical threshold was set as FDR (false discovery rate) < 0.05. Results: The DC values were significantly lower in the right superior frontal gyrus of PD patients compared to controls (FDR < 0.05). In addition, a negative correlation between the DC values and panic severity was observed in the right superior frontal gyrus and left inferior frontal gyrus. However, there was no significant association between the DC values and illness duration. Conclusion: The DC seemed significantly altered in the frontal lobe of PD patients. The role of the frontal lobe might be more emphasized in the pathophysiology research for PD.
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Affiliation(s)
- Yongbao Liu
- Department of Imaging, The First People's Hospital of LianYun Gang, Lianyungang City, Jiangsu Province, 222000, China
| | - Chien-Han Lai
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan.,PhD Psychiatry & Neuroscience Clinic, Taoyuan, Taiwan
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11
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Wu Y, Zhong Y, Zheng G, Liu Y, Pang M, Xu H, Ding H, Wang C, Zhang N. Disrupted fronto-temporal function in panic disorder: a resting-state connectome study. Brain Imaging Behav 2021; 16:888-898. [PMID: 34668168 DOI: 10.1007/s11682-021-00563-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2021] [Indexed: 12/21/2022]
Abstract
Recent neuroimaging studies have identified alterations in activity and connectivity among many brain regions as potential biomarkers for panic disorder. However, the functional connectome of panic disorder is not well understood. Therefore, a graph-theoretical approach was applied in this study to construct functional networks of patients and healthy controls in order to discover topological changes in panic disorder. 31 patients and 33 age and sex matched healthy controls underwent resting-state functional magnetic resonance imaging. Brain networks for each participant were structured using nodes from the Anatomical Automatic Labeling template and edges from connectivity matrices. Then, topological organizations of networks were calculated. Network-based statistical analysis was conducted, and global and nodal properties were compared between patients and controls. Unlike controls, patients with panic disorder displayed a small-world network. Patients also revealed decreased nodal efficiency in right superior frontal gyrus (SFG), middle frontal gyrus (MFG), right superior temporal gyrus (STG), and left middle temporal gyrus (MTG). Decreased functional connectivity was found in panic disorder between right MTG and extensive temporal regions. Among these disrupted regions, the decreased nodal efficiency of SFG showed a positive correlation with clinical symptoms while nodal betweenness centrality in angular gyrus showed a negative correlation. Our results indicated decreased function of global and regional information transmission in panic disorder and emphasized the role of temporal regions in its pathology.
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Affiliation(s)
- Yun Wu
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, No.264 Guangzhou Road, Gulou District, Nanjing, 210029, China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, China.,Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuan Zhong
- School of Psychology, Nanjing Normal University, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Mental Health and Cognitive Science, Nanjing Normal University, Nanjing, 210097, PR China
| | - Gang Zheng
- Department of Medical Imaging, Medical School of Nanjing University, Nanjing, Jiangsu, China.,College of Civil Aviation, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, China
| | - Ya Liu
- Department of Medical Imaging, Medical School of Nanjing University, Nanjing, Jiangsu, China.,College of Civil Aviation, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, China
| | - Manlong Pang
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, No.264 Guangzhou Road, Gulou District, Nanjing, 210029, China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, China.,Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huazhen Xu
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, No.264 Guangzhou Road, Gulou District, Nanjing, 210029, China.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huachen Ding
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, No.264 Guangzhou Road, Gulou District, Nanjing, 210029, China.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chun Wang
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, No.264 Guangzhou Road, Gulou District, Nanjing, 210029, China. .,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, China. .,Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Ning Zhang
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, No.264 Guangzhou Road, Gulou District, Nanjing, 210029, China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, China.,Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, Jiangsu, China
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12
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Dysregulation of threat neurociruitry during fear extinction: the role of anhedonia. Neuropsychopharmacology 2021; 46:1650-1657. [PMID: 33833400 PMCID: PMC8280223 DOI: 10.1038/s41386-021-01003-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/20/2021] [Accepted: 03/12/2021] [Indexed: 01/31/2023]
Abstract
Dimensional models of anxiety and depression highlight common and distinct symptom clusters that are thought to reflect disruptions in underlying functional processes. The current study investigated how functioning of threat neurocircuitry relates to symptom dimensions of anxiety and depression. Participants were aged 18-19 years (n = 229, 158 female) and were selected to ensure a range of scores on symptom measures. Symptom dimensions of "General Distress" (common to anxiety disorders and depression), "Fears" (more specific to anxiety disorders), and "Anhedonia-apprehension" (more specific to depression) were evaluated. Participants underwent functional magnetic resonance imaging during a Pavlovian fear conditioning paradigm. Multilevel modeling analyses estimated relationships between symptom dimensions and activation in threat neural circuitry. Exploratory whole brain analyses were also conducted. Threat-related neural activity was not associated with General Distress or Fears. Anhedonia-apprehension was associated with activation of bilateral amygdala, anterior insula and dACC during late extinction. We found no evidence to support an association between symptom dimensions of General Distress or Fears with threat circuitry activation in a large sample of young adults. We did, however, find that the symptom dimension of Anhedonia-apprehension was significantly associated with threat-related neural activation during fear extinction. This effect requires replication in future work but may reflect anhedonic impairments in learning when contingencies are altered, possibly linked to the rewarding relief of an unexpectedly absent threat.
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13
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Lai CH. Biomarkers in Panic Disorder. CURRENT PSYCHIATRY RESEARCH AND REVIEWS 2021. [DOI: 10.2174/2666082216999200918163245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Panic disorder (PD) is a kind of anxiety disorder that impacts the life quality
and functional perspectives in patients. However, the pathophysiological study of PD seems still
inadequate and many unresolved issues need to be clarified.
Objectives:
In this review article of biomarkers in PD, the investigator will focus on the findings of
magnetic resonance imaging (MRI) of the brain in the pathophysiology study. The MRI biomarkers
would be divided into several categories, on the basis of structural and functional perspectives.
Methods:
The structural category would include the gray matter and white matter tract studies. The
functional category would consist of functional MRI (fMRI), resting-state fMRI (Rs-fMRI), and
magnetic resonance spectroscopy (MRS). The PD biomarkers revealed by the above methodologies
would be discussed in this article.
Results:
For the gray matter perspectives, the PD patients would have alterations in the volumes of
fear network structures, such as the amygdala, parahippocampal gyrus, thalamus, anterior cingulate
cortex, insula, and frontal regions. For the white matter tract studies, the PD patients seemed to have
alterations in the fasciculus linking the fear network regions, such as the anterior thalamic radiation,
uncinate fasciculus, fronto-occipital fasciculus, and superior longitudinal fasciculus. For the fMRI
studies in PD, the significant results also focused on the fear network regions, such as the amygdala,
hippocampus, thalamus, insula, and frontal regions. For the Rs-fMRI studies, PD patients seemed to
have alterations in the regions of the default mode network and fear network model. At last, the
MRS results showed alterations in neuron metabolites of the hippocampus, amygdala, occipital
cortex, and frontal regions.
Conclusion:
The MRI biomarkers in PD might be compatible with the extended fear network model
hypothesis in PD, which included the amygdala, hippocampus, thalamus, insula, frontal regions, and
sensory-related cortex.
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Affiliation(s)
- Chien-Han Lai
- Department of Psychiatry, Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
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14
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Biggs EE, Timmers I, Meulders A, Vlaeyen JW, Goebel R, Kaas AL. The neural correlates of pain-related fear: A meta-analysis comparing fear conditioning studies using painful and non-painful stimuli. Neurosci Biobehav Rev 2020; 119:52-65. [DOI: 10.1016/j.neubiorev.2020.09.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 08/18/2020] [Accepted: 09/07/2020] [Indexed: 01/24/2023]
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15
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Won E, Kim YK. Neuroinflammation-Associated Alterations of the Brain as Potential Neural Biomarkers in Anxiety Disorders. Int J Mol Sci 2020; 21:ijms21186546. [PMID: 32906843 PMCID: PMC7555994 DOI: 10.3390/ijms21186546] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/30/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
Stress-induced changes in the immune system, which lead to neuroinflammation and consequent brain alterations, have been suggested as possible neurobiological substrates of anxiety disorders, with previous literature predominantly focusing on panic disorder, agoraphobia, and generalized anxiety disorder, among the anxiety disorders. Anxiety disorders have frequently been associated with chronic stress, with chronically stressful situations being reported to precipitate the onset of anxiety disorders. Also, chronic stress has been reported to lead to hypothalamic–pituitary–adrenal axis and autonomic nervous system disruption, which may in turn induce systemic proinflammatory conditions. Preliminary evidence suggests anxiety disorders are also associated with increased inflammation. Systemic inflammation can access the brain, and enhance pro-inflammatory cytokine levels that have been shown to precipitate direct and indirect neurotoxic effects. Prefrontal and limbic structures are widely reported to be influenced by neuroinflammatory conditions. In concordance with these findings, various imaging studies on panic disorder, agoraphobia, and generalized anxiety disorder have reported alterations in structure, function, and connectivity of prefrontal and limbic structures. Further research is needed on the use of inflammatory markers and brain imaging in the early diagnosis of anxiety disorders, along with the possible efficacy of anti-inflammatory interventions on the prevention and treatment of anxiety disorders.
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Affiliation(s)
- Eunsoo Won
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea;
| | - Yong-Ku Kim
- Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Ansan 15355, Korea
- Correspondence: ; Tel.: +82-31-412-5140; Fax: +82-31-412-5144
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16
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Merz CJ, Lonsdorf TB. Methodische Anmerkungen und Anwendungsbereiche der Furchtkonditionierung in verschiedenen psychologischen Disziplinen. PSYCHOLOGISCHE RUNDSCHAU 2020. [DOI: 10.1026/0033-3042/a000427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Zusammenfassung. Die Furchtkonditionierung stellt ein bedeutsames Paradigma zur Untersuchung von emotionalen Lern- und Gedächtnisprozessen dar. Nach einer ungefähr hundertjährigen Geschichte wird deutlich, dass die Furchtkonditionierung nicht nur einen wichtigen Beitrag zur speziesübergreifenden Grundlagenforschung liefert, sondern auch unterschiedliche Anwendungsfelder zu neuen Erkenntnissen inspirieren kann. In diesem Übersichtartikel soll das grundlegende Paradigma mit verschiedenen methodischen Überlegungen zur experimentellen Durchführung vorgestellt werden. Im Anschluss werden ausgewählte Anwendungsbereiche der Furchtkonditionierung innerhalb der psychologischen Disziplinen dargestellt: die Allgemeine Psychologie wird bezüglich allgemeingültiger Gesetzmäßigkeiten von Lern- und Gedächtnisprozessen angesprochen, die Differentielle Psychologie wegen bedeutsamer interindividueller Unterschiede, die Biologische Psychologie und Neuropsychologie in Bezug auf physiologische und anatomische Grundlagen der Furchtkonditionierung, die Sozialpsychologie im Zuge der Einstellungsforschung, die Entwicklungspsychologie aufgrund altersspezifischer Aspekte sowie die Klinische Psychologie und Psychotherapie im Hinblick auf die Pathogenese von Angsterkrankungen und der Expositionstherapie. Insgesamt betrachtet hat die Furchtkonditionierung das Potenzial nicht nur unterschiedliche Disziplinen der Psychologie in synergistischer Weise zusammenzubringen, sondern auch die verschiedenen inhaltlichen Schwerpunkte zu unterstreichen.
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Affiliation(s)
| | - Tina B. Lonsdorf
- Institut für systemische Neurowissenschaften, Universitätsklinikum Hamburg-Eppendorf
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17
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McIntosh RC, Hoshi RA, Timpano KR. Take my breath away: Neural activation at breath-hold differentiates individuals with panic disorder from healthy controls. Respir Physiol Neurobiol 2020; 277:103427. [PMID: 32120012 DOI: 10.1016/j.resp.2020.103427] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 02/12/2020] [Accepted: 02/24/2020] [Indexed: 01/04/2023]
Abstract
There is neuroanatomical evidence of an "extended fear network" of brain structures involved in the etiology of panic disorder (PD). Although ventilatory distrubance is a primary symptom of PD these sensations may also trigger onset of a panic attack (PA). Here, a voluntary breath-holding paradigm was used to mimic the hypercapnia state in order to compare blood oxygen level-dependent (BOLD) response, at the peak of a series of 18 s breath-holds, of 21 individuals with PD to 21 low anxiety matched controls. Compared to the rest condition, BOLD activity at the peak (12 - 18 s) of the breath-hold was greater for PD versus controls within a number of structures implicated in the extended fear network, including hippocampus, thalamus, and brainstem. Activation was also observed in cortical structures that are shown to be involved in interoceptive and self-referential processing, such as right insula, middle frontal gyrus, and precuneus/posterior cingulate. In lieu of amygdala activation, our findings show elevated activity throughout an extended network of cortical and subcortical structures involved in contextual, interoceptive and self-referential processing when individuals with PD engage in voluntary breath-holding.
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Affiliation(s)
- R C McIntosh
- Department of Psychology, University of Miami, 1120 NW 14th Street, Miami, FL, 33136, United States.
| | - R A Hoshi
- Clinical and Epidemiological Research Center, Sao Paulo University. 2565 Professor Lineu Prestes Ave, Sao Paulo, 05508-000, Brazil
| | - K R Timpano
- Department of Psychology, University of Miami, 1120 NW 14th Street, Miami, FL, 33136, United States
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18
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Schwarzmeier H, Kleint NI, Wittchen HU, Ströhle A, Hamm AO, Lueken U. Characterizing the nature of emotional-associative learning deficits in panic disorder: An fMRI study on fear conditioning, extinction training and recall. Eur Neuropsychopharmacol 2019; 29:306-318. [PMID: 30497840 DOI: 10.1016/j.euroneuro.2018.11.1108] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 11/12/2018] [Accepted: 11/13/2018] [Indexed: 12/22/2022]
Abstract
Emotional-associative learning represents a translational model for the development, maintenance and treatment of anxiety disorders such as panic disorder (PD). The exact nature of the underlying fear learning and extinction deficits however, remains under debate. Using a three-day paradigm to separate the distinct learning and consolidation processes, we aimed to gain insights into the neurofunctional substrates of altered fear conditioning, extinction training and recall in PD. In contrast to studies employing one-session fear conditioning paradigms, a differential fear conditioning and delayed extinction task was conducted for the purpose of disentangling neural networks involved in fear acquisition, extinction training and recall of extinction memories. Using functional magnetic resonance imaging (fMRI), quality-controlled datasets from 10 patients with PD and 10 healthy controls were available from three consecutive days (day 1: acquisition; day 2: extinction training; day 3: extinction recall) with neutral faces serving as CSs and an aversive auditory stimulus (panic scream) as US. PD patients showed heightened fear circuitry (e.g. right amygdala and left insula) activation during early acquisition and prolonged activation in the right insula, left inferior frontal operculum and left inferior frontal gyrus during extinction recall compared to healthy controls. Stronger neural activation in structures conferring defensive reactivity during early acquisition and extinction recall may indicate the accelerated acquisition of conditioned responses, while extinction recall may be attenuated as a function of PD pathophysiology. Future studies should investigate the predictive value of experimental measures of extinction recall for clinical relapse.
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Affiliation(s)
- H Schwarzmeier
- Center of Mental Health, Dept. of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Margarete-Höppel-Platz 1, D-97080 Würzburg, Germany.
| | - N I Kleint
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - H U Wittchen
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany; Clinical Psychology & Psychotherapy RG, Department of Psychiatry & Psychotherapy, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - A Ströhle
- Dept. of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
| | - A O Hamm
- Dept. of Physiological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald , Germany
| | - U Lueken
- Center of Mental Health, Dept. of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Margarete-Höppel-Platz 1, D-97080 Würzburg, Germany; Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany; Dept. of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
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19
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Picó-Pérez M, Alemany-Navarro M, Dunsmoor J, Radua J, Albajes-Eizagirre A, Vervliet B, Cardoner N, Benet O, Harrison B, Soriano-Mas C, Fullana M. Common and distinct neural correlates of fear extinction and cognitive reappraisal: A meta-analysis of fMRI studies. Neurosci Biobehav Rev 2019; 104:102-115. [DOI: 10.1016/j.neubiorev.2019.06.029] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 05/22/2019] [Accepted: 06/20/2019] [Indexed: 12/25/2022]
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20
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Kunas SL, Yang Y, Straube B, Kircher T, Gerlach AL, Pfleiderer B, Arolt V, Wittmann A, Stroehle A, Wittchen HU, Lueken U. The impact of depressive comorbidity on neural plasticity following cognitive-behavioral therapy in panic disorder with agoraphobia. J Affect Disord 2019; 245:451-460. [PMID: 30428445 DOI: 10.1016/j.jad.2018.11.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 10/09/2018] [Accepted: 11/03/2018] [Indexed: 01/14/2023]
Abstract
BACKGROUND Depressive disorders are a frequent comorbidity of panic disorder with agoraphobia (PD/AG). Cognitive-behavioral therapy (CBT) for PD/AG effectively reduces anxiety and depressive symptoms, irrespective of comorbidities. However, as depressive comorbidities can confound fear circuitry activation (i.e. amygdalae, insulae, anterior cingulate cortex) in PD/AG, we investigated whether comorbid depressive disorders alter neural plasticity following CBT. METHODS Within a randomized, controlled clinical trial on exposure-based CBT, forty-two PD/AG patients including fifteen (35.7%) with a comorbid depressive disorder (PD/AG + DEP) participated in a longitudinal functional magnetic resonance imaging (fMRI) study. A differential fear conditioning task was used as probe of interest. A generalized psycho-physiological interaction analysis (gPPI) served to study functional connectivity patterns. RESULTS After CBT, only PD/AG patients without comorbid depressive disorders (PD/AG-DEP) showed reduced activation in the left inferior frontal gyrus (IFG) extending to the insula. While PD/AG-DEP patients showed enhanced functional connectivity (FC) between the left IFG and subcortical structures (anterior cingulate cortex, thalamus and midbrain), PD/AG + DEP patients exhibited increased FC between the left IFG and cortical structures (prefrontal, parietal regions). In both groups, FC decreased following CBT. LIMITATIONS Primary depressed and medicated patients were excluded. Major depression and dysthymia were collapsed. CONCLUSIONS Reduced activation in the left IFG, as previously shown in PD/AG, appears to be a specific substrate of CBT effects in PD/AG-DEP patients only. Differential patterns of FC pertaining to fear circuitry networks in patients without depression vs. cognitive networks in patients with comorbid depression may point towards different pathways recruited by CBT as a function of comorbidity.
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Affiliation(s)
- Stefanie L Kunas
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Würzburg, Würzburg, Germany; Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
| | - Yunbo Yang
- Department of Psychiatry and Psychotherapy, Phillipps-University Marburg, Marburg, Germany
| | - Benjamin Straube
- Department of Psychiatry and Psychotherapy, Phillipps-University Marburg, Marburg, Germany
| | - Tilo Kircher
- Department of Psychiatry and Psychotherapy, Phillipps-University Marburg, Marburg, Germany
| | | | - Bettina Pfleiderer
- Department of Clinical Radiology, University Hospital Münster, Münster, Germany
| | - Volker Arolt
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Münster, Germany
| | - André Wittmann
- Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Stroehle
- Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Hans-Ulrich Wittchen
- Institute of Clinical Psychology and Psychotherapy, Department of Psychology, Technische Universität Dresden, Dresden, Germany
| | - Ulrike Lueken
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Würzburg, Würzburg, Germany; Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
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21
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Lucas EK, Clem RL. GABAergic interneurons: The orchestra or the conductor in fear learning and memory? Brain Res Bull 2018; 141:13-19. [PMID: 29197563 PMCID: PMC6178932 DOI: 10.1016/j.brainresbull.2017.11.016] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 11/15/2017] [Accepted: 11/28/2017] [Indexed: 10/18/2022]
Abstract
Fear conditioning is a form of associative learning that is fundamental to survival and involves potentiation of activity in excitatory projection neurons (PNs). Current models stipulate that the mechanisms underlying this process involve plasticity of PN synapses, which exhibit strengthening in response to fear conditioning. However, excitatory PNs are extensively modulated by a diverse array of GABAergic interneurons whose contributions to acquisition, storage, and expression of fear memory remain poorly understood. Here we review emerging evidence that genetically-defined interneurons play important subtype-specific roles in processing of fear-related stimuli and that these dynamics shape PN firing through both inhibition and disinhibition. Furthermore, interneurons exhibit structural, molecular, and electrophysiological evidence of fear learning-induced synaptic plasticity. These studies warrant discarding the notion of interneurons as passive bystanders in long-term memory.
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Affiliation(s)
- Elizabeth K Lucas
- Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, United States
| | - Roger L Clem
- Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, United States; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, United States.
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Fullana MA, Albajes-Eizagirre A, Soriano-Mas C, Vervliet B, Cardoner N, Benet O, Radua J, Harrison BJ. Fear extinction in the human brain: A meta-analysis of fMRI studies in healthy participants. Neurosci Biobehav Rev 2018. [PMID: 29530516 DOI: 10.1016/j.neubiorev.2018.03.002] [Citation(s) in RCA: 195] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The study of fear extinction represents an important example of translational neuroscience in psychiatry and promises to improve the understanding and treatment of anxiety and fear-related disorders. We present the results of a set of meta-analyses of human fear extinction studies in healthy participants, conducted with functional magnetic resonance imaging (fMRI) and reporting whole-brain results. Meta-analyses of fear extinction learning primarily implicate consistent activation of brain regions linked to threat appraisal and experience, including the dorsal anterior cingulate and anterior insular cortices. An overlapping anatomical result was obtained from the meta-analysis of extinction recall studies, except when studies directly compared an extinguished threat stimulus to an unextinguished threat stimulus (instead of a safety stimulus). In this latter instance, more consistent activation was observed in dorsolateral and ventromedial prefrontal cortex regions, together with other areas including the hippocampus. While our results partially support the notion of a shared neuroanatomy between human and rodent models of extinction processes, they also encourage an expanded account of the neural basis of human fear extinction.
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Affiliation(s)
- Miquel A Fullana
- FIDMAG Germanes Hospitalàries, CIBERSAM, Sant Boi de Llobregat, Barcelona, Spain; Department of Psychiatry, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | | | - Carles Soriano-Mas
- Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM, Barcelona, Spain; Department of Psychobiology and Methodology of Health Sciences, Universitat Autònoma de Barcelona, Spain
| | - Bram Vervliet
- Center for Excellence on Generalization in Health and Psychopathology, University of KU Leuven, Leuven, Belgium; Department of Psychiatry, Harvard Medical School, Boston, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, USA
| | - Narcís Cardoner
- Department of Psychiatry, Universitat Autònoma de Barcelona, Barcelona, Spain; Depression and Anxiety Unit, Mental Health Department, CIBERSAM, Parc Taulí Sabadell University Hospital, Barcelona, Spain
| | | | - Joaquim Radua
- FIDMAG Germanes Hospitalàries, CIBERSAM, Sant Boi de Llobregat, Barcelona, Spain; Institute of Psychiatry, King's College London, De Crespigny Park, London, UK; Centre for Psychiatric Research and Education, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Ben J Harrison
- Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Level 3, 161 Barry Street, Melbourne, Victoria, Australia.
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Feldker K, Heitmann CY, Neumeister P, Brinkmann L, Bruchmann M, Zwitserlood P, Straube T. Cardiorespiratory concerns shape brain responses during automatic panic-related scene processing in patients with panic disorder. J Psychiatry Neurosci 2018; 43. [PMID: 29252163 PMCID: PMC5747532 DOI: 10.1503/jpn.160226] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Increased automatic processing of threat-related stimuli has been proposed as a key element in panic disorder. Little is known about the neural basis of automatic processing, in particular to task-irrelevant, panic-related, ecologically valid stimuli, or about the association between brain activation and symptomatology in patients with panic disorder. METHODS The present event-related functional MRI (fMRI) study compared brain responses to task-irrelevant, panic-related and neutral visual stimuli in medication-free patients with panic disorder and healthy controls. Panic-related and neutral scenes were presented while participants performed a spatially nonoverlapping bar orientation task. Correlation analyses investigated the association between brain responses and panic-related aspects of symptomatology, measured using the Anxiety Sensitivity Index (ASI). RESULTS We included 26 patients with panic disorder and 26 heatlhy controls in our analysis. Compared with controls, patients with panic disorder showed elevated activation in the amygdala, brainstem, thalamus, insula, anterior cingulate cortex and midcingulate cortex in response to panic-related versus neutral task-irrelevant stimuli. Furthermore, fear of cardiovascular symptoms (a subcomponent of the ASI) was associated with insula activation, whereas fear of respiratory symptoms was associated with brainstem hyperactivation in patients with panic disorder. LIMITATIONS The additional implementation of measures of autonomic activation, such as pupil diameter, heart rate, or electrodermal activity, would have been informative during the fMRI scan as well as during the rating procedure. CONCLUSION Results reveal a neural network involved in the processing of panic-related distractor stimuli in patients with panic disorder and suggest an automatic weighting of panic-related information depending on the magnitude of cardiovascular and respiratory symptoms. Insula and brainstem activations show function-related associations with specific components of panic symptomatology.
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Affiliation(s)
- Katharina Feldker
- Correspondence to: K. Feldker, Institute of Medical Psychology and Systems Neuroscience, Von-Esmarch-Straße 52, D-48149 Muenster, Germany;
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Maron E, Lan CC, Nutt D. Imaging and Genetic Approaches to Inform Biomarkers for Anxiety Disorders, Obsessive-Compulsive Disorders, and PSTD. Curr Top Behav Neurosci 2018; 40:219-292. [PMID: 29796838 DOI: 10.1007/7854_2018_49] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Anxiety disorders are the most common mental health problem in the world and also claim the highest health care cost among various neuropsychiatric disorders. Anxiety disorders have a chronic and recurrent course and cause significantly negative impacts on patients' social, personal, and occupational functioning as well as quality of life. Despite their high prevalence rates, anxiety disorders have often been under-diagnosed or misdiagnosed, and consequently under-treated. Even with the correct diagnosis, anxiety disorders are known to be difficult to treat successfully. In order to implement better strategies in diagnosis, prognosis, treatment decision, and early prevention for anxiety disorders, tremendous efforts have been put into studies using genetic and neuroimaging techniques to advance our understandings of the underlying biological mechanisms. In addition to anxiety disorders including panic disorder, generalised anxiety disorder (GAD), specific phobias, social anxiety disorders (SAD), due to overlapping symptom dimensions, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) (which were removed from the anxiety disorder category in DSM-5 to become separate categories) are also included for review of relevant genetic and neuroimaging findings. Although the number of genetic or neuroimaging studies focusing on anxiety disorders is relatively small compare to other psychiatric disorders such as psychotic disorders or mood disorders, various structural abnormalities in the grey or white matter, functional alterations of activity during resting-state or task conditions, molecular changes of neurotransmitter receptors or transporters, and genetic associations have all been reported. With continuing effort, further genetic and neuroimaging research may potentially lead to clinically useful biomarkers for the prevention, diagnosis, and management of these disorders.
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Affiliation(s)
- Eduard Maron
- Neuropsychopharmacology Unit, Centre for Academic Psychiatry, Division of Brain Sciences, Imperial College London, London, UK.
- Department of Psychiatry, University of Tartu, Tartu, Estonia.
- Department of Psychiatry, North Estonia Medical Centre, Tallinn, Estonia.
| | - Chen-Chia Lan
- Neuropsychopharmacology Unit, Centre for Academic Psychiatry, Division of Brain Sciences, Imperial College London, London, UK
- Department of Psychiatry, Taichung Veterans General Hospital, Taichung, Taiwan
| | - David Nutt
- Neuropsychopharmacology Unit, Centre for Academic Psychiatry, Division of Brain Sciences, Imperial College London, London, UK
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Lueken U, Kuhn M, Yang Y, Straube B, Kircher T, Wittchen HU, Pfleiderer B, Arolt V, Wittmann A, Ströhle A, Weber H, Reif A, Domschke K, Deckert J, Lonsdorf TB. Modulation of defensive reactivity by GLRB allelic variation: converging evidence from an intermediate phenotype approach. Transl Psychiatry 2017; 7:e1227. [PMID: 28872638 PMCID: PMC5639239 DOI: 10.1038/tp.2017.186] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 06/07/2017] [Accepted: 07/04/2017] [Indexed: 01/20/2023] Open
Abstract
Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain's evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.
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Affiliation(s)
- U Lueken
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
| | - M Kuhn
- Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Y Yang
- Department of Psychiatry and Psychotherapy, Phillips-University Marburg, Marburg, Germany
| | - B Straube
- Department of Psychiatry and Psychotherapy, Phillips-University Marburg, Marburg, Germany
| | - T Kircher
- Department of Psychiatry and Psychotherapy, Phillips-University Marburg, Marburg, Germany
| | - H-U Wittchen
- Department of Psychology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - B Pfleiderer
- Department of Clinical Radiology, University Hospital Münster, Münster, Germany
| | - V Arolt
- Department of Psychiatry, University Hospital Münster, Münster, Germany
| | - A Wittmann
- Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
| | - A Ströhle
- Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Berlin, Germany
| | - H Weber
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - A Reif
- Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - K Domschke
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
- Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - J Deckert
- Center of Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany
| | - T B Lonsdorf
- Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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More than just noise: Inter-individual differences in fear acquisition, extinction and return of fear in humans - Biological, experiential, temperamental factors, and methodological pitfalls. Neurosci Biobehav Rev 2017; 80:703-728. [DOI: 10.1016/j.neubiorev.2017.07.007] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/12/2017] [Accepted: 07/20/2017] [Indexed: 01/07/2023]
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Sobanski T, Wagner G. Functional neuroanatomy in panic disorder: Status quo of the research. World J Psychiatry 2017; 7:12-33. [PMID: 28401046 PMCID: PMC5371170 DOI: 10.5498/wjp.v7.i1.12] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 11/16/2016] [Accepted: 01/11/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To provide an overview of the current research in the functional neuroanatomy of panic disorder. METHODS Panic disorder (PD) is a frequent psychiatric disease. Gorman et al (1989; 2000) proposed a comprehensive neuroanatomical model of PD, which suggested that fear- and anxiety-related responses are mediated by a so-called "fear network" which is centered in the amygdala and includes the hippocampus, thalamus, hypothalamus, periaqueductal gray region, locus coeruleus and other brainstem sites. We performed a systematic search by the electronic database PubMed. Thereby, the main focus was laid on recent neurofunctional, neurostructural, and neurochemical studies (from the period between January 2012 and April 2016). Within this frame, special attention was given to the emerging field of imaging genetics. RESULTS We noted that many neuroimaging studies have reinforced the role of the "fear network" regions in the pathophysiology of panic disorder. However, recent functional studies suggest abnormal activation mainly in an extended fear network comprising brainstem, anterior and midcingulate cortex (ACC and MCC), insula, and lateral as well as medial parts of the prefrontal cortex. Interestingly, differences in the amygdala activation were not as consistently reported as one would predict from the hypothesis of Gorman et al (2000). Indeed, amygdala hyperactivation seems to strongly depend on stimuli and experimental paradigms, sample heterogeneity and size, as well as on limitations of neuroimaging techniques. Advanced neurochemical studies have substantiated the major role of serotonergic, noradrenergic and glutamatergic neurotransmission in the pathophysiology of PD. However, alterations of GABAergic function in PD are still a matter of debate and also their specificity remains questionable. A promising new research approach is "imaging genetics". Imaging genetic studies are designed to evaluate the impact of genetic variations (polymorphisms) on cerebral function in regions critical for PD. Most recently, imaging genetic studies have not only confirmed the importance of serotonergic and noradrenergic transmission in the etiology of PD but also indicated the significance of neuropeptide S receptor, CRH receptor, human TransMEMbrane protein (TMEM123D), and amiloride-sensitive cation channel 2 (ACCN2) genes. CONCLUSION In light of these findings it is conceivable that in the near future this research will lead to the development of clinically useful tools like predictive biomarkers or novel treatment options.
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Lonsdorf TB, Menz MM, Andreatta M, Fullana MA, Golkar A, Haaker J, Heitland I, Hermann A, Kuhn M, Kruse O, Meir Drexler S, Meulders A, Nees F, Pittig A, Richter J, Römer S, Shiban Y, Schmitz A, Straube B, Vervliet B, Wendt J, Baas JMP, Merz CJ. Don't fear 'fear conditioning': Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear. Neurosci Biobehav Rev 2017; 77:247-285. [PMID: 28263758 DOI: 10.1016/j.neubiorev.2017.02.026] [Citation(s) in RCA: 543] [Impact Index Per Article: 67.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 02/23/2017] [Accepted: 02/28/2017] [Indexed: 12/24/2022]
Abstract
The so-called 'replicability crisis' has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.
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Affiliation(s)
- Tina B Lonsdorf
- University Medical Center Hamburg-Eppendorf, Department of Systems Neuroscience, Hamburg, Germany.
| | - Mareike M Menz
- University Medical Center Hamburg-Eppendorf, Department of Systems Neuroscience, Hamburg, Germany
| | - Marta Andreatta
- University of Würzburg, Department of Psychology, Biological Psychology, Clinical Psychology and Psychotherapy, Würzburg, Germany
| | - Miguel A Fullana
- Anxiety Unit, Institute of Neuropsychiatry and Addictions, Hospital del Mar, CIBERSAM, Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; Department of Psychiatry, Autonomous University of Barcelona, Barcelona, Spain
| | - Armita Golkar
- Karolinska Institutet, Department of Clinical Neuroscience, Psychology Section, Stockholm, Sweden; University of Amsterdam, Department of Clinical Psychology, Amsterdam, Netherlands
| | - Jan Haaker
- University Medical Center Hamburg-Eppendorf, Department of Systems Neuroscience, Hamburg, Germany; Karolinska Institutet, Department of Clinical Neuroscience, Psychology Section, Stockholm, Sweden
| | - Ivo Heitland
- Utrecht University, Department of Experimental Psychology and Helmholtz Institute, Utrecht, The Netherlands
| | - Andrea Hermann
- Justus Liebig University Giessen, Department of Psychology, Psychotherapy and Systems Neuroscience, Giessen, Germany
| | - Manuel Kuhn
- University Medical Center Hamburg-Eppendorf, Department of Systems Neuroscience, Hamburg, Germany
| | - Onno Kruse
- Justus Liebig University Giessen, Department of Psychology, Psychotherapy and Systems Neuroscience, Giessen, Germany
| | - Shira Meir Drexler
- Ruhr-University Bochum, Institute of Cognitive Neuroscience, Department of Cognitive Psychology, Bochum, Germany
| | - Ann Meulders
- KU Leuven, Health Psychology, Leuven, Belgium; Maastricht University, Research Group Behavioral Medicine, Maastricht, The Netherlands
| | - Frauke Nees
- Heidelberg University, Medical Faculty Mannheim, Central Institute of Mental Health, Department of Cognitive and Clinical Neuroscience, Mannheim, Germany
| | - Andre Pittig
- Technische Universität Dresden, Institute of Clinical Psychology and Psychotherapy, Dresden, Germany
| | - Jan Richter
- University of Greifswald, Department of Physiological and Clinical Psychology/Psychotherapy, Greifswald, Germany
| | - Sonja Römer
- Saarland University, Department of Clinical Psychology and Psychotherapy, Saarbrücken, Germany
| | - Youssef Shiban
- University of Regensburg, Department of Psychology, Clinical Psychology and Psychotherapy, Regensburg, Germany
| | - Anja Schmitz
- University of Regensburg, Department of Psychology, Clinical Psychology and Psychotherapy, Regensburg, Germany
| | - Benjamin Straube
- Philipps-University Marburg, Department of Psychiatry and Psychotherapy, Marburg, Germany
| | - Bram Vervliet
- KU Leuven, Centre for the Psychology of Learning and Experimental Psychopathology, Leuven, Belgium; Center for Excellence on Generalization, University of Leuven, Leuven, Belgium; Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - Julia Wendt
- University of Greifswald, Department of Physiological and Clinical Psychology/Psychotherapy, Greifswald, Germany
| | - Johanna M P Baas
- Utrecht University, Department of Experimental Psychology and Helmholtz Institute, Utrecht, The Netherlands
| | - Christian J Merz
- Ruhr-University Bochum, Institute of Cognitive Neuroscience, Department of Cognitive Psychology, Bochum, Germany
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Harrison BJ, Fullana MA, Via E, Soriano-Mas C, Vervliet B, Martínez-Zalacaín I, Pujol J, Davey CG, Kircher T, Straube B, Cardoner N. Human ventromedial prefrontal cortex and the positive affective processing of safety signals. Neuroimage 2017; 152:12-18. [PMID: 28254509 DOI: 10.1016/j.neuroimage.2017.02.080] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 02/21/2017] [Accepted: 02/26/2017] [Indexed: 12/20/2022] Open
Abstract
Human functional magnetic resonance imaging (fMRI) studies suggest that the ventromedial prefrontal cortex (vmPFC) contributes to the learned discrimination of threat and safety signals, although its precise contribution to these processes remains unclear. One hypothesis is that the vmPFC supports the positive affective processing of safety signals linked to their implicit stress-relieving properties. We set out to test this hypothesis and to examine the specificity of vmPFC responses to safety signal processing versus its high level of 'default mode' activity. Sixty participants completed an fMRI conditioning task that involved the generation of a conditioned threat (CS+) and safety (CS-) signal following the completion of a pre-conditioning baseline. Confirming past findings, activation of the vmPFC and other midline cortical and parietal areas - broadly resembling the default mode network - robustly discriminated between the CS- and CS+. However, when adjusting for this network's characteristic 'baseline' activity, only a subset of regions, including the vmPFC, was activated by the CS-. Regional selectivity for safety signal processing was confirmed by demonstrating a significant correlation between the magnitude of vmPFC responses and self-rated positive affect evoked by the CS-. Taken together, our current findings confirm a link between human vmPFC activity and the positive affective processing of safety signals. We discuss these findings with regards a broader model of human vmPFC function and its suggested higher-order contribution to emotionally adaptive behavior.
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Affiliation(s)
- Ben J Harrison
- Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Level 3, 161 Barry St. Carlton, VIC 3053, Australia.
| | - Miquel Angel Fullana
- Anxiety Unit, Institute of Neuropsychiatry and Addictions, Hospital del Mar, CIBERSAM G21, Barcelona 08003, Spain; Department of Psychiatry, Autonomous University of Barcelona, Barcelona 08193, Spain; Hospital del Mar Medical Research Unit (IMIM), Barcelona 08003, Spain
| | - Esther Via
- Department of Mental Health, Corporació Sanitaria Parc Taulí, Sabadell 08208, Spain; Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona 08907, Spain
| | - Carles Soriano-Mas
- Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona 08907, Spain; Department of Psychobiology and Methodology in Health Sciences, Universitat Autònoma de Barcelona, 08193, Spain
| | - Bram Vervliet
- Center for Excellence on Generalization, Department of Psychology, University of Leuven, Tiensestraat 102, Leuven 3000, Belgium
| | - Ignacio Martínez-Zalacaín
- Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona 08907, Spain
| | - Jesus Pujol
- MRI Research Unit, Department of Radiology, Hospital del Mar, CIBERSAM G21, Barcelona 08003, Spain
| | - Christopher G Davey
- Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Level 3, 161 Barry St. Carlton, VIC 3053, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Parkville 3052, Australia
| | - Tilo Kircher
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039, Marburg, Germany
| | - Benjamin Straube
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039, Marburg, Germany
| | - Narcís Cardoner
- Department of Mental Health, Corporació Sanitaria Parc Taulí, Sabadell 08208, Spain; Department of Psychiatry, Autonomous University of Barcelona, Barcelona 08193, Spain
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Klahn AL, Klinkenberg IA, Lueken U, Notzon S, Arolt V, Pantev C, Zwanzger P, Junghoefer M. Commonalities and differences in the neural substrates of threat predictability in panic disorder and specific phobia. NEUROIMAGE-CLINICAL 2017; 14:530-537. [PMID: 28331799 PMCID: PMC5345973 DOI: 10.1016/j.nicl.2017.02.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/15/2017] [Accepted: 02/16/2017] [Indexed: 10/27/2022]
Abstract
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.
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Affiliation(s)
- Anna Luisa Klahn
- Department of Psychiatry and Psychotherapy, University Hospital Muenster, Germany
| | | | - Ulrike Lueken
- Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, Germany
| | - Swantje Notzon
- Department of Psychiatry and Psychotherapy, University Hospital Muenster, Germany
| | - Volker Arolt
- Department of Psychiatry and Psychotherapy, University Hospital Muenster, Germany
| | - Christo Pantev
- Institute for Biogmagnetism and Biosignalanalysis, University of Muenster, Germany
| | - Peter Zwanzger
- Department of Psychiatry and Psychotherapy, University Hospital Muenster, Germany; kbo-Inn-Salzach-Hospital, Wasserburg am Inn, Germany; Department of Psychiatry and Psychotherapy, Ludwig Maximilian University of Munich, Germany
| | - Markus Junghoefer
- Institute for Biogmagnetism and Biosignalanalysis, University of Muenster, Germany
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Kim MK, Kim B, Kiu Choi T, Lee SH. White matter correlates of anxiety sensitivity in panic disorder. J Affect Disord 2017; 207:148-156. [PMID: 27721189 DOI: 10.1016/j.jad.2016.08.043] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 08/18/2016] [Accepted: 08/28/2016] [Indexed: 01/17/2023]
Abstract
BACKGROUND Anxiety sensitivity (AS) refers to a fear of anxiety-related sensations and is a dispositional variable especially elevated in patients with panic disorder (PD). Although several functional imaging studies of AS in patients with PD have suggested the presence of altered neural activity in paralimbic areas such as the insula, no study has investigated white matter (WM) alterations in patients with PD in relation to AS. The objective of this study was to investigate the WM correlates of AS in patients with PD. METHODS One-hundred and twelve right-handed patients with PD and 48 healthy control (HC) subjects were enrolled in this study. The Anxiety Sensitivity Inventory-Revised (ASI-R), the Panic Disorder Severity Scale (PDSS), the Albany Panic and Phobia Questionnaire (APPQ), the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory (BDI) were administered. Tract-based spatial statistics were used for diffusion tensor magnetic resonance imaging analysis. RESULTS Among the patients with PD, the ASI-R total scores were significantly correlated with the fractional anisotropy values of the WM regions near the insula, the splenium of the corpus callosum, the tapetum, the fornix/stria terminalis, the posterior limb of the internal capsule, the retrolenticular part of the internal capsule, the posterior thalamic radiation, the sagittal striatum, and the posterior corona radiata located in temporo-parieto-limbic regions and are involved in interoceptive processing (p<0.01; threshold-free cluster enhancement [TFCE]-corrected). These WM regions were also significantly correlated with the APPQ interoceptive avoidance subscale and BDI scores in patients with PD (p<0.01, TFCE-corrected). Correlation analysis among the HC subjects revealed no significant findings. LIMITATIONS There has been no comparative study on the structural neural correlates of AS in PD. CONCLUSIONS The current study suggests that the WM correlates of AS in patients with PD may be associated with the insula and the adjacent temporo-parieto-limbic WM regions, which may play important roles in interoceptive processing in the brain and in depression in PD.
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Affiliation(s)
- Min-Kyoung Kim
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Borah Kim
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Tai Kiu Choi
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Sang-Hyuk Lee
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
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Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing. Mol Psychiatry 2016; 21:813-22. [PMID: 26324098 DOI: 10.1038/mp.2015.125] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 06/23/2015] [Accepted: 07/06/2015] [Indexed: 12/18/2022]
Abstract
Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here we aimed to evaluate CRHR1 as a risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk allele of rs17689918 led to less flight behavior during fear-provoking situations but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus reduced gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.
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Influence of spatial frequency and emotion expression on face processing in patients with panic disorder. J Affect Disord 2016; 197:159-66. [PMID: 26991371 DOI: 10.1016/j.jad.2016.02.063] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 02/11/2016] [Accepted: 02/26/2016] [Indexed: 11/22/2022]
Abstract
BACKGROUND Deficits in facial emotion processing is a major characteristic of patients with panic disorder. It is known that visual stimuli with different spatial frequencies take distinct neural pathways. This study investigated facial emotion processing involving stimuli presented at broad, high, and low spatial frequencies in patients with panic disorder. METHODS Eighteen patients with panic disorder and 19 healthy controls were recruited. Seven event-related potential (ERP) components: (P100, N170, early posterior negativity (EPN); vertex positive potential (VPP), N250, P300; and late positive potential (LPP)) were evaluated while the participants looked at fearful and neutral facial stimuli presented at three spatial frequencies. RESULTS When a fearful face was presented, panic disorder patients showed a significantly increased P100 amplitude in response to low spatial frequency compared to high spatial frequency; whereas healthy controls demonstrated significant broad spatial frequency dependent processing in P100 amplitude. Vertex positive potential amplitude was significantly increased in high and broad spatial frequency, compared to low spatial frequency in panic disorder. Early posterior negativity amplitude was significantly different between HSF and BSF, and between LSF and BSF processing in both groups, regardless of facial expression. LIMITATION The possibly confounding effects of medication could not be controlled. CONCLUSIONS During early visual processing, patients with panic disorder prefer global to detailed information. However, in later processing, panic disorder patients overuse detailed information for the perception of facial expressions. These findings suggest that unique spatial frequency-dependent facial processing could shed light on the neural pathology associated with panic disorder.
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Liebscher C, Wittmann A, Gechter J, Schlagenhauf F, Lueken U, Plag J, Straube B, Pfleiderer B, Fehm L, Gerlach AL, Kircher T, Fydrich T, Deckert J, Wittchen HU, Heinz A, Arolt V, Ströhle A. Facing the fear--clinical and neural effects of cognitive behavioural and pharmacotherapy in panic disorder with agoraphobia. Eur Neuropsychopharmacol 2016; 26:431-44. [PMID: 26837851 DOI: 10.1016/j.euroneuro.2016.01.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 11/13/2015] [Accepted: 01/15/2016] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Cognitive behavioural therapy (CBT) and pharmacological treatment with selective serotonin or serotonin-noradrenalin reuptake inhibitors (SSRI/SSNRI) are regarded as efficacious treatments for panic disorder with agoraphobia (PD/AG). However, little is known about treatment-specific effects on symptoms and neurofunctional correlates. EXPERIMENTAL PROCEDURES We used a comparative design with PD/AG patients receiving either two types of CBT (therapist-guided (n=29) or non-guided exposure (n=22)) or pharmacological treatment (SSRI/SSNRI; n=28) as well as a wait-list control group (WL; n=15) to investigate differential treatment effects in general aspects of fear and depression (Hamilton Anxiety Rating Scale HAM-A and Beck Depression Inventory BDI), disorder-specific symptoms (Mobility Inventory MI, Panic and Agoraphobia Scale subscale panic attacks PAS-panic, Anxiety Sensitivity Index ASI, rating of agoraphobic stimuli) and neurofunctional substrates during symptom provocation (Westphal-Paradigm) using functional magnetic resonance imaging (fMRI). Comparisons of neural activation patterns also included healthy controls (n=29). RESULTS Both treatments led to a significantly greater reduction in panic attacks, depression and general anxiety than the WL group. The CBT groups, in particular, the therapist-guided arm, had a significantly greater decrease in avoidance, fear of phobic situations and anxiety symptoms and reduction in bilateral amygdala activation while the processing of agoraphobia-related pictures compared to the SSRI/SSNRI and WL groups. DISCUSSION This study demonstrates that therapist-guided CBT leads to a more pronounced short-term impact on agoraphobic psychopathology and supports the assumption of the amygdala as a central structure in a complex fear processing system as well as the amygdala's involvement in the fear system's sensitivity to treatment.
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Affiliation(s)
- Carolin Liebscher
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
| | - André Wittmann
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Johanna Gechter
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Florian Schlagenhauf
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany; Max Planck Institute for Human Cognitive and Brain Science, Leipzig, Germany
| | - Ulrike Lueken
- Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany
| | - Jens Plag
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Benjamin Straube
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
| | - Bettina Pfleiderer
- Department of Clinical Radiology, University of Münster, Münster, Germany
| | - Lydia Fehm
- Institute of Psychology, Psychotherapy and Somatopsychology - Humboldt University at Berlin, Berlin, Germany
| | | | - Tilo Kircher
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
| | - Thomas Fydrich
- Institute of Psychology, Psychotherapy and Somatopsychology - Humboldt University at Berlin, Berlin, Germany
| | - Jürgen Deckert
- Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany
| | - Hans-Ulrich Wittchen
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - Andreas Heinz
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Volker Arolt
- Department of Psychiatry, University of Münster, Münster, Germany
| | - Andreas Ströhle
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Greco JA, Liberzon I. Neuroimaging of Fear-Associated Learning. Neuropsychopharmacology 2016; 41:320-34. [PMID: 26294108 PMCID: PMC4677141 DOI: 10.1038/npp.2015.255] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 08/14/2015] [Accepted: 08/16/2015] [Indexed: 01/08/2023]
Abstract
Fear conditioning has been commonly used as a model of emotional learning in animals and, with the introduction of functional neuroimaging techniques, has proven useful in establishing the neurocircuitry of emotional learning in humans. Studies of fear acquisition suggest that regions such as amygdala, insula, anterior cingulate cortex, and hippocampus play an important role in acquisition of fear, whereas studies of fear extinction suggest that the amygdala is also crucial for safety learning. Extinction retention testing points to the ventromedial prefrontal cortex as an essential region in the recall of the safety trace, and explicit learning of fear and safety associations recruits additional cortical and subcortical regions. Importantly, many of these findings have implications in our understanding of the pathophysiology of psychiatric disease. Recent studies using clinical populations have lent insight into the changes in regional activity in specific disorders, and treatment studies have shown how pharmaceutical and other therapeutic interventions modulate brain activation during emotional learning. Finally, research investigating individual differences in neurotransmitter receptor genotypes has highlighted the contribution of these systems in fear-associated learning.
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Affiliation(s)
- John A Greco
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA
- VA Ann Arbor Healthcare System, Ann Arbor, MI, USA
| | - Israel Liberzon
- VA Ann Arbor Healthcare System, Ann Arbor, MI, USA
- Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA
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Nees F, Heinrich A, Flor H. A mechanism-oriented approach to psychopathology: The role of Pavlovian conditioning. Int J Psychophysiol 2015; 98:351-364. [DOI: 10.1016/j.ijpsycho.2015.05.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 05/01/2015] [Accepted: 05/06/2015] [Indexed: 01/19/2023]
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Lueken U, Straube B, Yang Y, Hahn T, Beesdo-Baum K, Wittchen HU, Konrad C, Ströhle A, Wittmann A, Gerlach AL, Pfleiderer B, Arolt V, Kircher T. Separating depressive comorbidity from panic disorder: A combined functional magnetic resonance imaging and machine learning approach. J Affect Disord 2015; 184:182-92. [PMID: 26093832 DOI: 10.1016/j.jad.2015.05.052] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 05/11/2015] [Accepted: 05/29/2015] [Indexed: 01/20/2023]
Abstract
BACKGROUND Depression is frequent in panic disorder (PD); yet, little is known about its influence on the neural substrates of PD. Difficulties in fear inhibition during safety signal processing have been reported as a pathophysiological feature of PD that is attenuated by depression. We investigated the impact of comorbid depression in PD with agoraphobia (AG) on the neural correlates of fear conditioning and the potential of machine learning to predict comorbidity status on the individual patient level based on neural characteristics. METHODS Fifty-nine PD/AG patients including 26 (44%) with a comorbid depressive disorder (PD/AG+DEP) underwent functional magnetic resonance imaging (fMRI). Comorbidity status was predicted using a random undersampling tree ensemble in a leave-one-out cross-validation framework. RESULTS PD/AG-DEP patients showed altered neural activation during safety signal processing, while +DEP patients exhibited generally decreased dorsolateral prefrontal and insular activation. Comorbidity status was correctly predicted in 79% of patients (sensitivity: 73%; specificity: 85%) based on brain activation during fear conditioning (corrected for potential confounders: accuracy: 73%; sensitivity: 77%; specificity: 70%). LIMITATIONS No primary depressed patients were available; only medication-free patients were included. Major depression and dysthymia were collapsed (power considerations). CONCLUSIONS Neurofunctional activation during safety signal processing differed between patients with or without comorbid depression, a finding which may explain heterogeneous results across previous studies. These findings demonstrate the relevance of comorbidity when investigating neurofunctional substrates of anxiety disorders. Predicting individual comorbidity status may translate neurofunctional data into clinically relevant information which might aid in planning individualized treatment. The study was registered with the ISRCTN ISRCTN80046034.
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Affiliation(s)
- Ulrike Lueken
- Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Würzburg, Füchsleinstr. 15, D-97080 Würzburg, Germany; Institute of Clinical Psychology and Psychotherapy, Department of Psychology, Technische Universität Dresden, Dresden, Germany.
| | - Benjamin Straube
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
| | - Yunbo Yang
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
| | - Tim Hahn
- Department of Cognitive Psychology II, Goethe-Universität Frankfurt, Frankfurt, Germany
| | - Katja Beesdo-Baum
- Institute of Clinical Psychology and Psychotherapy, Department of Psychology, Technische Universität Dresden, Dresden, Germany
| | - Hans-Ulrich Wittchen
- Institute of Clinical Psychology and Psychotherapy, Department of Psychology, Technische Universität Dresden, Dresden, Germany
| | - Carsten Konrad
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
| | - Andreas Ströhle
- Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-University Medicine Berlin, Berlin, Germany
| | - André Wittmann
- Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-University Medicine Berlin, Berlin, Germany
| | | | - Bettina Pfleiderer
- Department of Clinical Radiology, University Hospital Münster, Münster, Germany
| | - Volker Arolt
- Department of Psychiatry and Psychotherapy, University Hospital Münster, Münster, Germany
| | - Tilo Kircher
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
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Poletti S, Radaelli D, Cucchi M, Ricci L, Vai B, Smeraldi E, Benedetti F. Neural correlates of anxiety sensitivity in panic disorder: A functional magnetic resonance imaging study. Psychiatry Res 2015; 233:95-101. [PMID: 26071623 DOI: 10.1016/j.pscychresns.2015.05.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 09/01/2014] [Accepted: 05/22/2015] [Indexed: 12/22/2022]
Abstract
Panic disorder has been associated with dysfunctional neuropsychological dimensions, including anxiety sensitivity. Brain-imaging studies of the neural correlates of emotional processing have identified a network of structures that constitute the neural circuitry for emotions. The anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC) and insula, which are part of this network, are also involved in the processing of threat-related stimuli. The aim of the study was to investigate if neural activity in response to emotional stimuli in the cortico-limbic network is associated to anxiety sensitivity in panic disorder. In a sample of 18 outpatients with panic disorder, we studied neural correlates of implicit emotional processing of facial affect expressions with a face-matching paradigm; correlational analyses were performed between brain activations and anxiety sensitivity. The correlational analyses performed showed a positive correlation between anxiety sensitivity and brain activity during emotional processing in regions encompassing the PFC, ACC and insula. Our data seem to confirm that anxiety sensitivity is an important component of panic disorder. Accordingly, the neural underpinnings of anxiety sensitivity could be an interesting focus for treatment and further research.
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Affiliation(s)
- Sara Poletti
- Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milan, Italy.
| | - Daniele Radaelli
- Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milan, Italy
| | - Michele Cucchi
- Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy
| | - Liana Ricci
- Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy
| | - Benedetta Vai
- Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milan, Italy
| | - Enrico Smeraldi
- Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milan, Italy
| | - Francesco Benedetti
- Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milan, Italy
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Harrison BJ, Fullana MA, Soriano-Mas C, Via E, Pujol J, Martínez-Zalacaín I, Tinoco-Gonzalez D, Davey CG, López-Solà M, Pérez Sola V, Menchón JM, Cardoner N. A neural mediator of human anxiety sensitivity. Hum Brain Mapp 2015; 36:3950-8. [PMID: 26147233 DOI: 10.1002/hbm.22889] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 04/29/2015] [Accepted: 06/16/2015] [Indexed: 11/09/2022] Open
Abstract
Advances in the neuroscientific understanding of bodily autonomic awareness, or interoception, have led to the hypothesis that human trait anxiety sensitivity (AS)-the fear of bodily autonomic arousal-is primarily mediated by the anterior insular cortex. Despite broad appeal, few experimental studies have comprehensively addressed this hypothesis. We recruited 55 individuals exhibiting a range of AS and assessed them with functional magnetic resonance imaging (fMRI) during aversive fear conditioning. For each participant, three primary measures of interest were derived: a trait Anxiety Sensitivity Index score; an in-scanner rating of elevated bodily anxiety sensations during fear conditioning; and a corresponding estimate of whole-brain functional activation to the conditioned versus nonconditioned stimuli. Using a voxel-wise mediation analysis framework, we formally tested for 'neural mediators' of the predicted association between trait AS score and in-scanner anxiety sensations during fear conditioning. Contrary to the anterior insular hypothesis, no evidence of significant mediation was observed for this brain region, which was instead linked to perceived anxiety sensations independently from AS. Evidence for significant mediation was obtained for the dorsal anterior cingulate cortex-a finding that we argue is more consistent with the hypothesized role of human cingulofrontal cortex in conscious threat appraisal processes, including threat-overestimation. This study offers an important neurobiological validation of the AS construct and identifies a specific neural substrate that may underlie high AS clinical phenotypes, including but not limited to panic disorder.
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Affiliation(s)
- Ben J Harrison
- Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Victoria, Australia
| | - Miquel A Fullana
- Institute of Neuropsychiatry and Addictions, Hospital Del Mar, CIBERSAM G21, Barcelona, Spain.,Department of Psychiatry, Autonomous University of Barcelona, Barcelona, Spain.,Hospital Del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Carles Soriano-Mas
- Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona, Spain.,Department of Psychobiology and Methodology of Health Sciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Esther Via
- Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona, Spain
| | - Jesus Pujol
- MRI Research Unit, CRC Mar, Hospital Del Mar, CIBERSAM G21, Barcelona, Spain
| | | | | | - Christopher G Davey
- Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Victoria, Australia.,Orygen Youth Health Research Centre, Centre for Youth Mental Health, The University of Melbourne, Victoria, Australia
| | - Marina López-Solà
- Department of Psychology and Neuroscience., University of Colorado, Colorado
| | - Victor Pérez Sola
- Institute of Neuropsychiatry and Addictions, Hospital Del Mar, CIBERSAM G21, Barcelona, Spain
| | - José M Menchón
- Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona, Spain
| | - Narcís Cardoner
- Department of Psychiatry, Bellvitge University Hospital-IDIBELL, CIBERSAM G17, Barcelona, Spain
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The brain acid–base homeostasis and serotonin: A perspective on the use of carbon dioxide as human and rodent experimental model of panic. Prog Neurobiol 2015; 129:58-78. [DOI: 10.1016/j.pneurobio.2015.04.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 04/16/2015] [Accepted: 04/20/2015] [Indexed: 12/14/2022]
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Straube B, Lueken U, Jansen A, Konrad C, Gloster AT, Gerlach AL, Ströhle A, Wittmann A, Pfleiderer B, Gauggel S, Wittchen U, Arolt V, Kircher T. Neural correlates of procedural variants in cognitive-behavioral therapy: a randomized, controlled multicenter FMRI study. PSYCHOTHERAPY AND PSYCHOSOMATICS 2015; 83:222-33. [PMID: 24970601 DOI: 10.1159/000359955] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 01/19/2014] [Indexed: 11/19/2022]
Abstract
BACKGROUND Cognitive behavioral therapy (CBT) is an effective treatment for panic disorder with agoraphobia (PD/AG). It is unknown, how variants of CBT differentially modulate brain networks involved in PD/AG. This study was aimed to evaluate the effects of therapist-guided (T+) versus self-guided (T-) exposure on the neural correlates of fear conditioning in PD/AG. METHOD In a randomized, controlled multicenter clinical trial in medication-free patients with PD/AG who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before (t1) and after CBT (t2). Quality-controlled fMRI data from 42 patients and 42 healthy subjects (HS) were obtained. Patients were randomized to two variants of CBT (T+, n = 22, and T-, n = 20). RESULTS The interaction of diagnosis (PD/AG, HS), treatment group (T+, T-), time point (t1, t2) and stimulus type (conditioned stimulus: yes, no) revealed activation in the left hippocampus and the occipitotemporal cortex. The T+ group demonstrated increased activation of the hippocampus at t2 (t2 > t1), which was positively correlated with treatment outcome, and a decreased connectivity between the left inferior frontal gyrus and the left hippocampus across time (t1 > t2). CONCLUSION After T+ exposure, contingency-encoding processes related to the posterior hippocampus are augmented and more decoupled from processes of the left inferior frontal gyrus, previously shown to be dysfunctionally activated in PD/AG. Linking single procedural variants to neural substrates offers the potential to inform about the optimization of targeted psychotherapeutic interventions.
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Affiliation(s)
- Benjamin Straube
- Department of Psychiatry and Psychotherapy, Philipps University Marburg, Marburg, Germany
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Duits P, Cath DC, Lissek S, Hox JJ, Hamm AO, Engelhard IM, van den Hout MA, Baas JMP. Updated meta-analysis of classical fear conditioning in the anxiety disorders. Depress Anxiety 2015; 32:239-53. [PMID: 25703487 DOI: 10.1002/da.22353] [Citation(s) in RCA: 495] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 12/09/2014] [Accepted: 12/20/2014] [Indexed: 12/14/2022] Open
Abstract
The aim of the current study was twofold: (1) to systematically examine differences in fear conditioning between anxiety patients and healthy controls using meta-analytic methods, and (2) to examine the extent to which study characteristics may account for the variability in findings across studies. Forty-four studies (published between 1920 and 2013) with data on 963 anxiety disordered patients and 1,222 control subjects were obtained through PubMed and PsycINFO, as well as from a previous meta-analysis on fear conditioning (Lissek et al.). Results demonstrated robustly increased fear responses to conditioned safety cues (CS-) in anxiety patients compared to controls during acquisition. This effect may represent an impaired ability to inhibit fear in the presence of safety cues (CS-) and/or may signify an increased tendency in anxiety disordered patients to generalize fear responses to safe stimuli resembling the conditioned danger cue (CS+). In contrast, during extinction, patients show stronger fear responses to the CS+ and a trend toward increased discrimination learning (differentiation between the CS+ and CS-) compared to controls, indicating delayed and/or reduced extinction of fear in anxiety patients. Finally, none of the included study characteristics, such as the type of fear measure (subjective vs. psychophysiological index of fear), could account significantly for the variance in effect sizes across studies. Further research is needed to investigate the predictive value of fear extinction on treatment outcome, as extinction processes are thought to underlie the beneficial effects of exposure treatment in anxiety disorders.
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Affiliation(s)
- Puck Duits
- Department of Clinical and Health Psychology, Faculty of Social Sciences, Utrecht University, Utrecht, The Netherlands
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Straube B, Reif A, Richter J, Lueken U, Weber H, Arolt V, Jansen A, Zwanzger P, Domschke K, Pauli P, Konrad C, Gerlach AL, Lang T, Fydrich T, Alpers GW, Ströhle A, Wittmann A, Pfleiderer B, Wittchen HU, Hamm A, Deckert J, Kircher T. The functional -1019C/G HTR1A polymorphism and mechanisms of fear. Transl Psychiatry 2014; 4:e490. [PMID: 25514753 PMCID: PMC4270311 DOI: 10.1038/tp.2014.130] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 10/23/2014] [Accepted: 10/26/2014] [Indexed: 01/01/2023] Open
Abstract
Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n=185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n=245; after CBT: n=171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n=39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders.
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Affiliation(s)
- B Straube
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany,Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Strasse 8, 35039 Marburg, Germany. E-mail:
| | - A Reif
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
| | - J Richter
- Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany
| | - U Lueken
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - H Weber
- Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany
| | - V Arolt
- Department of Psychiatry, University of Münster, Münster, Germany
| | - A Jansen
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
| | - P Zwanzger
- Department of Psychiatry, University of Münster, Münster, Germany
| | - K Domschke
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
| | - P Pauli
- Department of Psychology, University of Würzburg, Würzburg, Germany
| | - C Konrad
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany,Department of Psychiatry, University of Münster, Münster, Germany
| | - A L Gerlach
- Department of Psychology, University of Cologne, Cologne, Germany
| | - T Lang
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany,University of Bremen and Christoph-Dornier Foundation for Clinical Psychology, Bremen, Germany
| | - T Fydrich
- Department of Psychology, Humboldt University, Berlin, Germany
| | - G W Alpers
- Department of Psychology, Clinical and Biological Psychology, School of Social Sciences, Mannheim, Germany
| | - A Ströhle
- Department of Psychiatry and Psychotherapy, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - A Wittmann
- Department of Psychiatry and Psychotherapy, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - B Pfleiderer
- Department of Clinical Radiology, University of Münster, Münster, Germany
| | - H-U Wittchen
- Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany
| | - A Hamm
- Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany
| | - J Deckert
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
| | - T Kircher
- Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
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The neural correlates of cognitive behavioral therapy: Recent progress in the investigation of patients with panic disorder. Behav Res Ther 2014; 62:88-96. [DOI: 10.1016/j.brat.2014.07.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 07/10/2014] [Accepted: 07/16/2014] [Indexed: 12/16/2022]
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Frontal white matter alterations in short-term medicated panic disorder patients without comorbid conditions: a diffusion tensor imaging study. PLoS One 2014; 9:e95279. [PMID: 24788587 PMCID: PMC4005735 DOI: 10.1371/journal.pone.0095279] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 03/25/2014] [Indexed: 01/04/2023] Open
Abstract
The frontal cortex might play an important role in the fear network, and white matter (WM) integrity could be related to the pathophysiology of panic disorder (PD). A few studies have investigated alterations of WM integrity in PD. The aim of this study was to determine frontal WM integrity differences between patients with PD without comorbid conditions and healthy control (HC) subjects by using diffusion tensor imaging. Thirty-six patients with PD who had used medication within 1 week and 27 age- and sex-matched HC subjects participated in this study. Structural brain magnetic resonance imaging was performed on all participants. Panic Disorder Severity Scale and Beck Anxiety Inventory (BAI) scores were assessed. Tract-based spatial statistics (TBSS) was used for image analysis. TBSS analysis showed decreased fractional anisotropy (FA) in frontal WM and WM around the frontal lobe, including the corpus callosum of both hemispheres, in patients with PD compared to HC subjects. Moreover, voxel-wise correlation analysis revealed that the BAI scores for patients with PD were positively correlated with their FA values for regions showing group differences in the FA of frontal WM of both hemispheres. Altered integrity in frontal WM of patients with PD without comorbid conditions might represent the structural pathophysiology in these patients, and these changes could be related to clinical symptoms of PD.
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Altered olfactory processing of stress-related body odors and artificial odors in patients with panic disorder. PLoS One 2013; 8:e74655. [PMID: 24086358 PMCID: PMC3782473 DOI: 10.1371/journal.pone.0074655] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 08/08/2013] [Indexed: 01/04/2023] Open
Abstract
Background Patients with Panic Disorder (PD) direct their attention towards potential threat, followed by panic attacks, and increased sweat production. Onés own anxiety sweat odor influences the attentional focus, and discrimination of threat or non-threat. Since olfactory projection areas overlap with neuronal areas of a panic-specific fear network, the present study investigated the neuronal processing of odors in general and of stress-related sweat odors in particular in patients with PD. Methods A sample of 13 patients with PD with/ without agoraphobia and 13 age- and gender-matched healthy controls underwent an fMRI investigation during olfactory stimulation with their stress-related sweat odors (TSST, ergometry) as well as artificial odors (peach, artificial sweat) as non-fearful non-body odors. Principal Findings The two groups did not differ with respect to their olfactory identification ability. Independent of the kind of odor, the patients with PD showed activations in fronto-cortical areas in contrast to the healthy controls who showed activations in olfaction-related areas such as the amygdalae and the hippocampus. For artificial odors, the patients with PD showed a decreased neuronal activation of the thalamus, the posterior cingulate cortex and the anterior cingulate cortex. Under the presentation of sweat odor caused by ergometric exercise, the patients with PD showed an increased activation in the superior temporal gyrus, the supramarginal gyrus, and the cingulate cortex which was positively correlated with the severity of the psychopathology. For the sweat odor from the anxiety condition, the patients with PD showed an increased activation in the gyrus frontalis inferior, which was positively correlated with the severity of the psychopathology. Conclusions The results suggest altered neuronal processing of olfactory stimuli in PD. Both artificial odors and stress-related body odors activate specific parts of a fear-network which is associated with an increased severity of the psychopathology.
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