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U Lueken,
B Straube,
I Reinhardt,
N I Maslowski,
H-U Wittchen,
A Ströhle,
A Wittmann,
B Pfleiderer, C Konrad,
A Ewert,
C Uhlmann,
V Arolt,
A Jansen,
T Kircher
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ABSTRACT: BACKGROUND: Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients. Method The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls. RESULTS: Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation. CONCLUSIONS: The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.
Psychological Medicine 04/2013; · 6.16 Impact Factor
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A Reif,
J Richter,
B Straube,
M Höfler,
U Lueken,
A T Gloster,
H Weber,
K Domschke,
L Fehm,
A Ströhle, [......],
A Wittmann,
B Pfleiderer,
G W Alpers,
P Pauli,
T Lang,
V Arolt,
H-U Wittchen,
A Hamm,
T Kircher,
J Deckert
[show abstract]
[hide abstract]
ABSTRACT: Panic disorder with agoraphobia (PD/AG) is a prevalent mental disorder featuring a substantial complex genetic component. At present, only a few established risk genes exist. Among these, the gene encoding monoamine oxidase A (MAOA) is noteworthy given that genetic variation has been demonstrated to influence gene expression and monoamine levels. Long alleles of the MAOA-uVNTR promoter polymorphism are associated with PD/AG and correspond with increased enzyme activity. Here, we have thus investigated the impact of MAOA-uVNTR on therapy response, behavioral avoidance and brain activity in fear conditioning in a large controlled and randomized multicenter study on cognitive behavioral therapy (CBT) in PD/AG. The study consisted of 369 PD/AG patients, and genetic information was available for 283 patients. Carriers of the risk allele had significantly worse outcome as measured by the Hamilton Anxiety scale (46% responders vs 67%, P=0.017). This was accompanied by elevated heart rate and increased fear during an anxiety-provoking situation, that is, the behavioral avoidance task. All but one panic attack that happened during this task occurred in risk allele carriers and, furthermore, risk allele carriers did not habituate to the situation during repetitive exposure. Finally, functional neuroimaging during a classical fear conditioning paradigm evidenced that the protective allele is associated with increased activation of the anterior cingulate cortex upon presentation of the CS+ during acquisition of fear. Further differentiation between high- and low-risk subjects after treatment was observed in the inferior parietal lobes, suggesting differential brain activation patterns upon CBT. Taken together, we established that a genetic risk factor for PD/AG is associated with worse response to CBT and identify potential underlying neural mechanisms. These findings might govern how psychotherapy can include genetic information to tailor individualized treatment approaches.Molecular Psychiatry advance online publication, 15 January 2013; doi:10.1038/mp.2012.172.
Molecular psychiatry 01/2013; · 15.05 Impact Factor
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ABSTRACT: OBJECTIVES: Spinobulbar muscular atrophy [Kennedy's disease (KD)] is a rare X-linked neurodegenerative disorder of mainly spinal and bulbar motoneurons. Recent studies suggest a multisystem character of this disease. The aim of this study was to identify and characterize structural changes of gray (GM) and white matter (WM) in the central nervous system. MATERIAL AND METHODS: Whole-brain-based voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analyses were applied to MRI data of eight genetically proven patients with KD and compared with 16 healthy age-matched controls. RESULTS: Diffusion tensor imaging analysis showed not only decreased fractional anisotropy (FA) values in the brainstem, but also widespread changes in central WM tracts, whereas VBM analysis of the WM showed alterations primarily in the brainstem and cerebellum. There were no changes in GM volume. The FA value decrease in the brainstem correlated with the disease duration. CONCLUSION: Diffusion tensor imaging analysis revealed subtle changes of central WM tract integrity, while GM and WM volume remained unaffected. In our patient sample, KD had more extended effects than previously reported. These changes could either be attributed primarily to neurodegeneration or reflect secondary plastic changes due to atrophy of lower motor neurons and reorganization of cortical structures.
Acta Neurologica Scandinavica 12/2012; · 2.47 Impact Factor
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[show abstract]
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ABSTRACT: Die depressive Störung gehört zu den häufigsten und schwerwiegendsten psychischen Erkrankungen. Trotz eines starken genetischen
Einflusses blieb die Suche nach Kandidatengenen bisher von begrenztem Erfolg. Im Kontext komplexer, polygenetischer Erbgänge
und heterogener, klinisch definierter Phänotypen wie der depressiven Störung scheint der Endophänotypansatz Erfolg versprechender
zu sein. Die Entdeckung, dass eine genetische Risikovariante für Depressionen im Serotonintransportergen (5-HTTLPR) mit einer verstärkten Amygdalareaktivität auf aversive Reize assoziiert ist, legte den Grundstein für das Forschungsgebiet
„imaging genetics“, welches durch die Wahl neurobiologischer Aktivierungsmuster als Endophänotyp charakterisiert ist. In der
vorliegenden Übersicht werden bisherige Ergebnisse aus diesem rapide wachsenden Forschungsbereich diskutiert, wobei vor allem
genetische Effekte auf die Funktion kortikolimbischer Netzwerke bei der Emotionsverarbeitung betrachtet werden. Es zeigt sich,
dass mögliche Risikogenvarianten auch bei Gesunden zu funktionellen Veränderungen führen, die mit den Befunden bei depressiven
Patienten vergleichbar sind.
Major depression is one of the most frequent and serious psychiatric diseases. Although the disease is highly heritable, the
search for candidate genes has been of limited success hitherto. The complex, polygenetic hereditary transmissions coding
for heterogeneous, clinically defined phenotypes such as major depression may be better identified using the endophenotype
approach. A recent study, reporting an association of the risk allele in a serotonin transporter polymorphism (5-HTTLPR) with increased amygdala responsiveness to aversive stimuli, stimulated the new research field of imaging genetics, which
is characterized by the choice of neurobiological activity patterns as endophenotypes. This review discusses recent studies
from this rapidly growing research field, focussing on genetic effects on cortico-limbic circuitries during emotion processing.
Evidence is reviewed suggesting that potential risk-alleles for depression are associated with functional cortico-limbic abnormalities,
which frequently occur in patients with major depression.
Der Nervenarzt 04/2012; 81(1):24-31. · 0.68 Impact Factor
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[hide abstract]
ABSTRACT: Hypnotic paralysis has been used since the times of Charcot to study altered states of consciousness; however, the underlying neurobiological correlates are poorly understood. We investigated human brain function during hypnotic paralysis using resting-state functional magnetic resonance imaging (fMRI), focussing on two core regions of the default mode network and the representation of the paralysed hand in the primary motor cortex. Hypnotic suggestion induced an observable left-hand paralysis in 19 participants. Resting-state fMRI at 3T was performed in pseudo-randomised order awake and in the hypnotic condition. Functional connectivity analyses revealed increased connectivity of the precuneus with the right dorsolateral prefrontal cortex, angular gyrus, and a dorsal part of the precuneus. Functional connectivity of the medial frontal cortex and the primary motor cortex remained unchanged. Our results reveal that the precuneus plays a pivotal role during maintenance of an altered state of consciousness. The increased coupling of selective cortical areas with the precuneus supports the concept that hypnotic paralysis may be mediated by a modified representation of the self which impacts motor abilities.
NeuroImage 06/2011; 56(4):2173-82. · 5.89 Impact Factor
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C Sehlmeyer,
U Dannlowski,
S Schöning,
H Kugel,
M Pyka,
B Pfleiderer,
P Zwitserlood,
H Schiffbauer,
W Heindel,
V Arolt, C Konrad
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[hide abstract]
ABSTRACT: Fear conditioning involves the amygdala as the main neural structure for learning fear responses whereas fear extinction mainly activates the inhibitory prefrontal cortex (PFC). In this study we investigated whether individual differences in trait anxiety affect amygdala and dorsal anterior cingulate cortex (dACC) activation during fear conditioning and extinction.
Thirty-two healthy subjects were investigated by functional magnetic resonance imaging (fMRI) at 3 T while performing a cued fear-conditioning task. All participants completed the trait version of the State-Trait Anxiety Inventory (STAI-T). Activations of the amygdala and the dACC were examined with respect to the effects of trait anxiety.
Analysis of the fMRI data demonstrated enhanced activation in fear-related brain areas, such as the insula and the ACC, during both fear conditioning and extinction. Activation of the amygdala appeared only during the late acquisition phase whereas deactivation was observed during extinction. Regression analyses revealed that highly trait-anxious subjects exhibited sustained amygdala activation and reduced dACC involvement during the extinction of conditioned responses.
This study reveals that high levels of trait anxiety are associated with both increased amygdala activation and reduced dACC recruitment during the extinction of conditioned fear. This hyper-responsivity of the amygdala and the deficient cognitive control during the extinction of conditioned fear in anxious subjects reflect an increased resistance to extinct fear responses and may thereby enhance the vulnerability to developing anxiety disorders.
Psychological Medicine 04/2011; 41(4):789-98. · 6.16 Impact Factor
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ABSTRACT: The stop-signal task is a prototypical experiment to study cognitive processes that mediate successful performance in a rapidly changing environment. By means of simultaneous recording and combined analysis of electroencephalography and functional magnetic resonance imaging on single trial level, we provide a comprehensive view on brain responses related to performance monitoring in this task. Three types of event-related EEG components were analyzed: a go-related N2/P3-complex devoid of motor-inhibition, the stop-related N2/P3-complex and the error-related negativity with its consecutive error positivity. Relevant functional networks were identified by crossmodal correlation analyses in a parallel independent component analysis framework. Go-related potentials were associated with a midcingulate network known to participate in the processing of conflicts, a left-dominant somatosensory-motor network, and deactivations in visual cortices. Stop-related brain responses in association with the N2/P3-complex were seen with networks known to support motor and cognitive inhibition, including parts of the basal ganglia, the anterior midcingulate cortex and pre-supplementary motor area as well as the anterior insula. Error-related brain responses showed a similar constellation with additional recruitment of the posterior insula and the inferior frontal cortex. Our data clearly indicate that the pre-supplementary motor area is involved in inhibitory mechanisms but not in the processing of conflicts per se.
NeuroImage 03/2011; 56(3):1588-97. · 5.89 Impact Factor
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ABSTRACT: The tumor necrosis factor alpha (TNF-α) is a cytokine that exerts neuroprotective and neurodegenerative effects. While some research suggests enhancing effects of the TNF-α gene (TNF-α -308G→A) on cognitive function, further research is needed to clarify the association between the TNF-α gene and specific areas of cognitive performance including their neurophysiological correlates. In this study we examine association of the TNF-α -308G→A single nucleotide polymorphism (rs1800629) with attention and mental rotation performance in an event-related potential (ERP) study in healthy participants (n=67). The results show that carriers of the -308 A allele display elevated attentional processes (i.e. a stronger N1) as compared to the GG genotype group. Mental rotation performance varied across genotypes when demands on mental rotation were high. Here, carriers of the -308 A allele performed better than the GG genotype group. This is paralleled by the neurophysiological data showing genotype-dependent variations in parietal positivities only under the condition of high demands on mental rotation. The finding of enhanced attentional and mental rotation performance in A allele carriers supports recent findings that the A allele of this single nucleotide polymorphism (SNP) enhances cognitive performance on a general measure of cognitive processing speed.
Neuroscience 10/2010; 170(3):742-8. · 3.38 Impact Factor
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ABSTRACT: BACKGROUND: The objective of this study was to investigate long-term cognitive and emotional sequelae of mild traumatic brain injury (mTBI), as previous research has remained inconclusive with respect to their prevalence and extent.MethodThirty-three individuals who had sustained mTBI on average 6 years prior to the study and 33 healthy control subjects were matched according to age, gender and education. Structural brain damage at time of testing was excluded by magnetic resonance imaging (MRI). A comprehensive neuropsychological test battery was conducted to assess learning, recall, working memory, attention and executive function. Psychiatric symptoms were assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the Beck Depression Inventory (BDI). Possible negative response bias was ruled out by implementing the Word Memory Test (WMT). RESULTS: The mTBI individuals had significant impairments in all cognitive domains compared to the healthy control subjects. Effect sizes of cognitive deficits were medium to large, and could not be accounted for by self-perceived deficits, depression, compensation claims or negative response bias. BDI scores were significantly higher in the patient group, and three patients fulfilled DSM-IV criteria for a mild episode of major depression. CONCLUSIONS: Primarily, well-recovered individuals who had sustained a minor trauma more than half a decade ago continue to have long-term cognitive and emotional sequelae relevant for everyday social and professional life. mTBI may lead to a lasting disruption of neurofunctional circuits not detectable by standard structural MRI and needs to be taken seriously in clinical and forensic evaluations.
Psychological Medicine 09/2010; · 6.16 Impact Factor
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ABSTRACT: Both the N200 and P300, which are, for example, evoked by Go/Nogo or Stop-Signal tasks, have long been interpreted as indicators for inhibition processes. Such interpretations have recently been challenged, and interest in the exact neural generators of these brain responses is continuously growing. Using recent methodological advancements, source estimations for the N200 and P300 as evoked by a tactile response inhibition task were computed. Current density reconstructions were also calculated accounting for interindividual differences in head geometry by incorporating information from T1-weighted magnetic resonance images. To ease comparability with relevant paradigms, the task was designed to mimic important characteristics of both Go/Nogo and Stop-Signal tasks as prototypes for a larger set of paradigms probing response inhibition. A network of neural generators was revealed, which has previously been shown to act in concert with executive control processes and thus is in full agreement with observations from other modalities. Importantly, a spatial segregation of midcingulate sources was observed. Our experimental data indicate that a left anterior region of the midcingulate cortex (MCC) is a major neural generator of the N200, whereas the midcingulate generator of the P300 is located in the right posterior MCC. Analyses of the P300 also revealed several areas, which have previously been associated with motor functions, for example, the precentral region. Our data clearly suggest a neuroanatomical and therefore also functional dissociation of the N200 and P300, a finding that cannot easily be provided by other imaging techniques.
Human Brain Mapping 08/2010; 31(8):1260-71. · 5.88 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Set-shifting and maintenance are complex cognitive processes, which are often impaired in schizophrenia. The genetic basis of these processes is poorly understood. We aimed to investigate the association between genetic variants of the metabotropic glutamate receptor 3 (GRM3) and cognitive set-shifting in healthy individuals. The relationship between 14 selected single nucleotide polymorphisms (SNPs) of the GRM3 gene and cognitive set-shifting as measured by perseverative errors using the modified card sorting test (MCST) was analysed in a sample of N = 98 young healthy individuals (mean age in years: 22.7 +/- 0.19). Results show that SNP rs17676277 is related to the performance on the MCST. Subjects with the TT genotype showed significantly less perseverative errors as compared with the AA (P = 0.025) and AT (P = 0.0005) and combined AA/AT genotypes (P = 0.0005). Haplotype analyses suggest the involvement of various SNPs of the GRM3 gene in perseverative error processing in a dominant model of inheritance. The findings strongly suggest that the genetic variation (rs17676277 and three haplotypes) in the metabotropic GRM3 is related to cognitive set-shifting in healthy individuals independent of working memory. However, because of a relatively small sample size for a genetic association study, the present results are tentative and require replication.
Genes Brain and Behavior 07/2010; 9(5):459-66. · 3.48 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Anxiety is often associated with impaired cognitive control and avoidance behaviour. The aim of this study was to investigate the effect of anxiety-related personality traits, such as anxiety sensitivity and trait anxiety, on event-related potentials of response inhibition in a standard Go/Nogo-paradigm. We focused on the Nogo-N2 and Nogo-P3 components, which probably represent different sub-processes of response inhibition. The Nogo-N2 was mainly influenced by trait anxiety, while it was slightly affected by anxiety sensitivity. In contrast, the Nogo-P3 was significantly associated with anxiety sensitivity, but was less affected by trait anxiety. Thus, anxious subjects seem to maintain a higher level of cognitive control to prepare and to monitor the outcome of their actions, which is differentially reflected in Nogo-N2 and Nogo-P3 potentials. Our results show that anxiety-related personality traits modulate electrophysiological responses related to cognitive control processes and should be taken into consideration in studies investigating response inhibition.
Neuropsychologia 04/2010; 48(9):2488-95. · 3.64 Impact Factor
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[hide abstract]
ABSTRACT: Response inhibition is a basic executive function which is dysfunctional in various basal ganglia diseases. The brain-derived-neurotrophic-factor (BDNF) plays an important pathophysiological role in these diseases. In the current study we examined the functional relevance of the BDNF val66met polymorphism for response inhibition processes in 57 healthy human subjects using event-related potentials (ERPs), i.e. the Nogo-N2 and Nogo-P3, which likely reflect different aspects of inhibition. Our results support the pre-motor inhibition theory of the Nogo-N2. We show that the BDNF val66met polymorphism selectively modulates the Nogo-N2. Response inhibition was better in the val/met-met/met group, since this group committed fewer false alarms, and their Nogo-N2 was larger, compared to the val/val group. This is the first study showing that met alleles of the BDNF val66met polymorphism confer an advantage for a specific cognitive function. We propose a neuronal model how this advantage gets manifest on a neuronal level.
Neuroscience 03/2010; 166(1):178-84. · 3.38 Impact Factor
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AV Rauch,
V Paul,
L Horst,
J Bauer,
P Ohrmann, C Konrad,
U Dannlowski,
B Egloff,
W Heindel,
V Arolt,
others
Klinische Neurophysiologie 01/2010; 41(01):ID37. · 0.14 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Major depression is one of the most frequent and serious psychiatric diseases. Although the disease is highly heritable, the search for candidate genes has been of limited success hitherto. The complex, polygenetic hereditary transmissions coding for heterogeneous, clinically defined phenotypes such as major depression may be better identified using the endophenotype approach. A recent study, reporting an association of the risk allele in a serotonin transporter polymorphism (5-HTTLPR) with increased amygdala responsiveness to aversive stimuli, stimulated the new research field of imaging genetics, which is characterized by the choice of neurobiological activity patterns as endophenotypes. This review discusses recent studies from this rapidly growing research field, focussing on genetic effects on cortico-limbic circuitries during emotion processing. Evidence is reviewed suggesting that potential risk-alleles for depression are associated with functional cortico-limbic abnormalities, which frequently occur in patients with major depression.
Der Nervenarzt 12/2009; 81(1):24-31. · 0.68 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Due to its crucial role for memory processes and its relevance in neurological and psychiatric disorders, the hippocampus has been the focus of neuroimaging research for several decades. In vivo measurement of human hippocampal volume and shape with magnetic resonance imaging has become an important element of neuroimaging research. Nevertheless, volumetric findings are still inconsistent and controversial for many psychiatric conditions including affective disorders. Here we review the wealth of anatomical protocols for the delineation of the hippocampus in MR images, taking into consideration 71 different published protocols from the neuroimaging literature, with an emphasis on studies of affective disorders. We identified large variations between protocols in five major areas. 1) The inclusion/exclusion of hippocampal white matter (alveus and fimbria), 2) the definition of the anterior hippocampal-amygdala border, 3) the definition of the posterior border and the extent to which the hippocampal tail is included, 4) the definition of the inferior medial border of the hippocampus, and 5) the use of varying arbitrary lines. These are major sources of variance between different protocols. In contrast, the definitions of the lateral, superior, and inferior borders are less disputed. Directing resources to replication studies that incorporate characteristics of the segmentation protocols presented herein may help resolve seemingly contradictory volumetric results between prior neuroimaging studies and facilitate the appropriate selection of protocols for manual or automated delineation of the hippocampus for future research purposes.
NeuroImage 06/2009; 47(4):1185-95. · 5.89 Impact Factor
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U Dannlowski, C Konrad,
D Rumstadt,
P Ohrmann,
S Schoning,
J Bauer,
H Kugel,
W Heindel,
V Arolt,
P Zwitserlood,
others
NeuroImage 01/2009; 47:S71-S71. · 5.89 Impact Factor
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C Konrad,
A Engelien,
S Schöning,
P Zwitserlood,
A Jansen,
E Pletziger,
P Beizai,
A Kersting,
P Ohrmann,
E Luders,
R R Greb,
W Heindel,
V Arolt,
H Kugel
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[hide abstract]
ABSTRACT: This study examines the neurobiology of semantic retrieval and describes the influence of gender, menstrual cycle, and sex hormones on semantic networks. Healthy right-handed subjects (12 men, 12 women) were investigated with 3T-fMRI during synonym generation. Behavioral performance and sex hormone levels were assessed. Women were examined during the early follicular and midluteal cycle phase. The activation pattern in all groups involved left frontal and temporal as well as bilateral medial frontal, cingulate, occipital, basal ganglia, and cerebellar regions. Men showed greater left frontal activation than women in both menstrual cycle phases. Women yielded high correlations of left prefrontal activation with estradiol in the midluteal phase and with progesterone in both phases. Testosterone levels correlated highly with left prefrontal activation in all three groups. In all, we describe a cerebral network involved in semantic processing and demonstrate that it is significantly affected by gender and sex steroid hormones.
Acta Neurovegetativa 07/2008; 115(9):1327-37. · 2.73 Impact Factor
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AV Rauch,
M Reker,
P Ohrmann,
A Pedersen,
J Bauer,
U Dannlowski,
K Kölkebeck, C Konrad,
H Kugel,
V Arolt,
others
Klinische Neurophysiologie 01/2008; 39(01):A203. · 0.14 Impact Factor
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U Dannlowski,
P Ohrmann,
J Bauer, C Konrad,
S Schöning,
J Deckert,
C Hohoff,
H Kugel,
V Arolt,
W Heindel,
others
Klinische Neurophysiologie 01/2008; 39(01):A206. · 0.14 Impact Factor
