Publications by authors named "Swantje Notzon"

10 Publications

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Modulating Emotion Perception: Opposing Effects of Inhibitory and Excitatory Prefrontal Cortex Stimulation.

Biol Psychiatry Cogn Neurosci Neuroimaging 2018 04 29;3(4):329-336. Epub 2017 Dec 29.

Institute for Biomagnetism and Biosignal Analysis and Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience, University of Muenster, Muenster, Germany. Electronic address:

Background: Excitatory repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (dlPFC) is approved by the U.S. Food and Drug Administration for the treatment of adult patients with treatment-resistant major depressive disorder (MDD). This stimulation is supposed to restore excitability of prefrontal cortex regions that exhibit diminished regulation of emotion-generative systems in MDD. Based on the valence lateralization hypothesis, inhibitory rTMS of the right dlPFC has also been applied in MDD. This approach has proved to be effective, although meta-analyses of emotional perception and affective regulation in healthy control subjects and patients with depression do not support functional asymmetries within dlPFC regions.

Methods: To shed more light on this discrepancy, the effects of excitatory and inhibitory rTMS of the right dlPFC on visual emotional perception were compared in two groups of 41 healthy participants overall. Before and after rTMS stimulation, participants viewed fearful and neutral faces while whole-head magnetoencephalography was recorded and supplemented by behavioral tests.

Results: Visual sensory processing of fearful facial expressions, relative to neutral facial expressions, was reduced after excitatory stimulation and was increased after inhibitory stimulation within right occipital and right temporal regions. Correspondingly, after excitatory rTMS compared with inhibitory rTMS, participants displayed relatively reduced reaction times in an emotion discrimination task and showed reduced emotional arousal.

Conclusions: These results support the hypothesis that excitatory rTMS compared with inhibitory rTMS of the right dlPFC strengthens top-down control of aversive stimuli in healthy control subjects, which should encourage more research on mechanisms of excitatory/inhibitory dlPFC-rTMS protocols in general and on neuromodulatory treatment of MDD.
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http://dx.doi.org/10.1016/j.bpsc.2017.12.007DOI Listing
April 2018

Neurobiological and clinical effects of fNIRS-controlled rTMS in patients with panic disorder/agoraphobia during cognitive-behavioural therapy.

Neuroimage Clin 2017 22;16:668-677. Epub 2017 Sep 22.

Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, Albert-Schweitzer-Campus 1, University of Muenster, Muenster, Germany.

Background: A relevant proportion of patients with panic disorder (PD) does not improve even though they receive state of the art treatment for anxiety disorders such as cognitive-behavioural therapy (CBT). At the same time, it is known, that from a neurobiological point of view, PD patients are often characterised by prefrontal hypoactivation. Intermittent Theta Burst Stimulation (iTBS) is a non-invasive type of neurostimulation which can modulate cortical activity and thus has the potential to normalise prefrontal hypoactivity found in PD. We therefore aimed at investigating the effects of iTBS as an innovative add-on to CBT in the treatment for PD.

Methods: In this double-blind, bicentric study, 44 PD patients, randomised to sham or verum stimulation, received 15 sessions of iTBS over the left prefrontal cortex (PFC) in addition to 9 weeks of group CBT. Cortical activity during a cognitive as well as an emotional (Emotional Stroop) paradigm was assessed both at baseline and post-iTBS treatment using functional near-infrared spectroscopy (fNIRS) and compared to healthy controls.

Results: In this manuscript we only report the results of the emotional paradigm; for the results of the cognitive paradigm please refer to Deppermann et al. (2014). During the Emotional Stroop test, PD patients showed significantly reduced activation to panic-related compared to neutral stimuli for the left PFC at baseline. Bilateral prefrontal activation for panic-related stimuli significantly increased after verum iTBS only. Clinical ratings significantly improved during CBT and remained stable at follow-up. However, no clinical differences between the verum- and sham-stimulated group were identified, except for a more stable reduction of agoraphobic avoidance during follow-up in the verum iTBS group.

Limitations: Limitations include insufficient blinding, the missing control for possible state-dependent iTBS effects, and the timing of iTBS application during CBT.

Conclusion: Prefrontal hypoactivity in PD patients was normalised by add-on iTBS. Clinical improvement of anxiety symptoms was not affected by iTBS.
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http://dx.doi.org/10.1016/j.nicl.2017.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650598PMC
June 2018

Commonalities and differences in the neural substrates of threat predictability in panic disorder and specific phobia.

Neuroimage Clin 2017 20;14:530-537. Epub 2017 Feb 20.

Institute for Biogmagnetism and Biosignalanalysis, University of Muenster, Germany.

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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http://dx.doi.org/10.1016/j.nicl.2017.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345973PMC
November 2017

Emotional processing and rTMS: does inhibitory theta burst stimulation affect the human startle reflex?

J Neural Transm (Vienna) 2016 10 13;123(10):1121-31. Epub 2016 May 13.

Department of Psychiatry and Psychotherapy, University of Muenster, Albert-Schweitzer-Campus 1, Gebaeude A9, 48149, Muenster, Germany.

Repetitive transcranial magnetic stimulation (rTMS) enables the local and non-invasive modulation of cortical activity and has proved to achieve antidepressant effects. To a lesser extent, rTMS is investigated as a treatment option for anxiety disorders. As the prefrontal cortex and the amygdala represent key components of human emotion regulation, we investigated how prefrontally applied rTMS affects the responsiveness of the subcortical amygdala during a fear-relevant study paradigm to examine potential cortico-limbic effects. Sham-controlled, randomised inhibitory rTMS (continuous theta burst stimulation, TBS) was applied to 102 healthy subjects (female = 54) over the right dorsolateral prefrontal cortex. Subsequently, the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) acoustic startle response was investigated. Subjective anxiety ratings (anxiety sensitivity, trait and state anxiety) were considered. Picture category affected the startle magnitude as expected for both TBS intervention groups (highest startle response for unpleasant, lowest for pleasant pictures). However, no modulatory effects of TBS on startle potentiation were discerned. No significant interaction effects of TBS intervention, subjective anxiety ratings, and gender were identified. Interestingly, startle habituation was influenced by TBS intervention on a trend-level, with verum TBS leading to an accelerated habituation. We found no evidence for the hypothesis that prefrontal inhibitory TBS affects the responsiveness of the amygdala during the presentation of emotionally relevant stimuli in healthy subjects. Instead, we found accelerated habituation under verum TBS on a statistical trend-level. Hence, some preliminary hints for modulatory effects of inhibitory TBS on basic learning mechanisms could be found.
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http://dx.doi.org/10.1007/s00702-016-1568-8DOI Listing
October 2016

Prepare for scare-Impact of threat predictability on affective visual processing in spider phobia.

Behav Brain Res 2016 07 29;307:84-91. Epub 2016 Mar 29.

Institute for Biogmagnetism and Biosignalanalysis, University of Muenster, Germany. Electronic address:

The visual processing of emotional faces is influenced by individual's level of stress and anxiety. Valence unspecific affective processing is expected to be influenced by predictability of threat. Using a design of phasic fear (predictable threat), sustained anxiety (unpredictable threat) and safety (no threat), we investigated the magnetoencephalographic correlates and temporal dynamics of emotional face processing in a sample of phobic patients. Compared to non-anxious controls, phobic individuals revealed decreased parietal emotional attention processes during affective processing at mid-latency and late processing stages. While control subjects showed increasing parietal processing of the facial stimuli in line with decreasing threat predictability, phobic subjects revealed the opposite pattern. Decreasing threat predictability also led to increasing neural activity in the orbitofrontal and dorsolateral prefrontal cortex at mid-latency stages. Additionally, unpredictability of threat lead to higher subjective discomfort compared to predictability of threat and no threat safety condition. Our findings indicate that visual processing of emotional information is influenced by both stress induction and pathologic anxiety.
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http://dx.doi.org/10.1016/j.bbr.2016.03.045DOI Listing
July 2016

Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic.

Eur Neuropsychopharmacol 2015 Oct 20;25(10):1677-82. Epub 2015 Jul 20.

Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany; kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University of Munich, Munich, Germany. Electronic address:

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.
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http://dx.doi.org/10.1016/j.euroneuro.2015.07.011DOI Listing
October 2015

SPIDER OR NO SPIDER? NEURAL CORRELATES OF SUSTAINED AND PHASIC FEAR IN SPIDER PHOBIA.

Depress Anxiety 2015 Sep 26;32(9):656-63. Epub 2015 Jun 26.

Department of Psychiatry, University of Münster, Münster, Germany.

Background: Processes of phasic fear responses to threatening stimuli are thought to be distinct from sustained, anticipatory anxiety toward an unpredicted, potential threat. There is evidence for dissociable neural correlates of phasic fear and sustained anxiety. Whereas increased amygdala activity has been associated with phasic fear, sustained anxiety has been linked with activation of the bed nucleus of stria terminalis (BNST), anterior cingulate cortex (ACC), and the insula. So far, only a few studies have focused on the dissociation of neural processes related to both phasic and sustained fear in specific phobia. We suggested that first, conditions of phasic and sustained fear would involve different neural networks and, second, that overall neural activity would be enhanced in a sample of phobic compared to nonphobic participants.

Methods: Pictures of spiders and neutral stimuli under conditions of either predicted (phasic) or unpredicted (sustained) fear were presented to 28 subjects with spider phobia and 28 nonphobic control subjects during functional magnetic resonance imaging (fMRI) scanning.

Results: Phobic patients revealed significantly higher amygdala activation than controls under conditions of phasic fear. Sustained fear processing was significantly related to activation in the insula and ACC, and phobic patients showed a stronger activation than controls of the BNST and the right ACC under conditions of sustained fear. Functional connectivity analysis revealed enhanced connectivity of the BNST and the amygdala in phobic subjects.

Conclusions: Our findings support the idea of distinct neural correlates of phasic and sustained fear processes. Increased neural activity and functional connectivity in these networks might be crucial for the development and maintenance of anxiety disorders.
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http://dx.doi.org/10.1002/da.22382DOI Listing
September 2015

Multilevel impact of the dopamine system on the emotion-potentiated startle reflex.

Psychopharmacology (Berl) 2015 Jun 17;232(11):1983-93. Epub 2014 Dec 17.

Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080, Wuerzburg, Germany,

Rationale/objectives: The pathogenetic mechanism of emotion-related disorders such as anxiety disorders is considered to be complex with an interaction of genetic, biochemical, and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic system-partly conferred by catechol-O-methyltransferase (COMT) gene variation-and for distorted emotional processing to constitute risk factors for anxiety and anxiety-related disorders.

Methods: Applying a multilevel approach, we analyzed the main and interactive effects of the functional COMT val158met polymorphism and L-dopa (single-dose 50 mg levodopa and 12.5 mg carbidopa; double-blind, placebo-controlled design) on the emotion-potentiated (unpleasant, neutral, and pleasant IAPS pictures) startle response as an intermediate phenotype of anxiety in a sample of 100 healthy probands (f = 52, m = 48).

Results: The COMT 158val allele was associated with an increased startle potentiation by unpleasant stimuli as compared with neutral stimuli irrespective of L-dopa or placebo intervention. COMT 158met/met genotype carriers, while displaying no difference in startle magnitude in response to unpleasant or neutral pictures in the placebo condition, showed startle potentiation by unpleasant pictures under L-dopa administration only.

Conclusions: The present proof-of-concept study provides preliminary support for a complex, multilevel impact of the dopaminergic system on the emotion-potentiated startle reflex suggesting increased phasic dopamine transmission driven by the more active COMT 158val allele and/or a single dose of L-dopa to predispose to maladaptive emotional processing and thereby potentially also to anxiety-related psychopathological states.
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http://dx.doi.org/10.1007/s00213-014-3830-9DOI Listing
June 2015

Does rTMS alter neurocognitive functioning in patients with panic disorder/agoraphobia? An fNIRS-based investigation of prefrontal activation during a cognitive task and its modulation via sham-controlled rTMS.

Biomed Res Int 2014 18;2014:542526. Epub 2014 Mar 18.

Department of Psychiatry and Psychotherapy, University of Tuebingen, Calwerstr 14, 72076 Tuebingen, Germany ; Graduate School LEAD, University of Tuebingen, Europastr. 6, 72072 Tuebingen, Germany ; Cluster of Excellence CIN, University of Tuebingen, Otfried-Mueller-Str. 25, 72076 Tuebingen, Germany.

Objectives: Neurobiologically, panic disorder (PD) is supposed to be characterised by cerebral hypofrontality. Via functional near-infrared spectroscopy (fNIRS), we investigated whether prefrontal hypoactivity during cognitive tasks in PD-patients compared to healthy controls (HC) could be replicated. As intermittent theta burst stimulation (iTBS) modulates cortical activity, we furthermore investigated its ability to normalise prefrontal activation.

Methods: Forty-four PD-patients, randomised to sham or verum group, received 15 iTBS-sessions above the left dorsolateral prefrontal cortex (DLPFC) in addition to psychoeducation. Before first and after last iTBS-treatment, cortical activity during a verbal fluency task was assessed via fNIRS and compared to the results of 23 HC.

Results: At baseline, PD-patients showed hypofrontality including the DLPFC, which differed significantly from activation patterns of HC. However, verum iTBS did not augment prefrontal fNIRS activation. Solely after sham iTBS, a significant increase of measured fNIRS activation in the left inferior frontal gyrus (IFG) during the phonological task was found.

Conclusion: Our results support findings that PD is characterised by prefrontal hypoactivation during cognitive performance. However, verum iTBS as an "add-on" to psychoeducation did not augment prefrontal activity. Instead we only found increased fNIRS activation in the left IFG after sham iTBS application. Possible reasons including task-related psychophysiological arousal are discussed.
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http://dx.doi.org/10.1155/2014/542526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976939PMC
December 2014

Acute anxiolytic effects of quetiapine during virtual reality exposure--a double-blind placebo-controlled trial in patients with specific phobia.

Eur Neuropsychopharmacol 2013 Nov 30;23(11):1551-60. Epub 2013 Jan 30.

Department of Psychiatry, University of Muenster, Germany.

Anxiety disorders are among the most frequent psychiatric disorders. With regard to pharmacological treatment, antidepressants, the calcium modulator pregabalin and benzodiazepines are recommended according to current treatment guidelines. With regard to acute states of anxiety, so far practically only benzodiazepines provide an immediate anxiolytic effect. However, the risk of tolerance and dependency limits the use of this class of medication. Therefore, there is still a need for alternative pharmacologic strategies. Increasing evidence points towards anxiety-reducing properties of atypical antipsychotics, particularly quetiapine. Therefore, we aimed to evaluate the putative acute anxiolytic effects of this compound, choosing the induction of acute anxiety in patients with specific phobia as a model for the evaluation of ad-hoc anxiolytic properties in a proof-of-concept approach. In a randomized, double-blind, placebo-controlled study, 58 patients with arachnophobia were treated with a single dose of quetiapine XR or placebo prior to a virtual reality spider challenge procedure. Treatment effects were monitored using rating scales for acute anxiety as well as measurements of heart rate and skin conductance. Overall, quetiapine showed significant anxiolytic effects compared to placebo. However, effects were not seen on the primary outcome measure (VAS Anxiety), but were limited to somatic anxiety symptoms. Additionally, a significant reduction of skin conductance was observed. Further exploratory analyses hint towards a mediating role of the (COMT) val158met genotype on treatment response. The present results thus suggest a possible suitability of quetiapine in the acute treatment of anxiety, particularly with regard to somatic symptoms.
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http://dx.doi.org/10.1016/j.euroneuro.2013.01.001DOI Listing
November 2013