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Martin J. Herrmann

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13 papers

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YNIMG Journal 2024 Journal Article

Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders

Kevin Hilbert
Joscha Böhnlein
Charlotte Meinke
Alice V. Chavanne
Till Langhammer
Lara Stumpe
Nils Winter
Ramona Leenings

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

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YNICL Journal 2022 Journal Article

Neural correlates of fear conditioning are associated with treatment-outcomes to behavioral exposure in spider phobia – Evidence from magnetoencephalography

Kati Roesmann
Julius Toelle
Elisabeth Johanna Leehr
Ida Wessing
Joscha Böhnlein
Fabian Seeger
Hanna Schwarzmeier
Niklas Siminski

BACKGROUND: Models of anxiety disorders and the rationale of exposure therapy (ET) are grounded on classical fear conditioning. Yet, it is unclear whether lower fear ratings of conditioned safety versus threat cues and corresponding neural markers of safety-learning and/or fear inhibition assessed before treatment would predict better outcomes of behavioral exposure. METHODS: Sixty-six patients with spider phobia completed pre-treatment clinical and experimental fear conditioning assessments, one session of virtual reality ET, a post-treatment clinical assessment, and a 6-month follow-up assessment. Tilted Gabor gratings served as conditioned stimuli (CS) that were either paired (CS+) or remained unpaired (CS-) with an aversive phobia-related and phobia-unrelated unconditioned stimulus (UCS). CS+/CS- differences in fear ratings and magnetoencephalographic event-related fields (ERFs) were related to percentual symptom reductions from pre- to post-treatment, as assessed via spider phobia questionnaire (SPQ), behavioral avoidance test (BAT), and remission status at 6-month follow-up. RESULTS: We observed no associations between pre-treatment CS+/CS- differences in fear ratings and any treatment outcome. CS+/CS- differences in source estimations of ERFs revealed that higher CS- activity in bilateral dorsolateral prefrontal cortex (dlPFC) was related with SPQ- and BAT-reductions. Associations between CS+/CS- differences and treatment outcomes were also observed in left ventromedial prefrontal cortex (vmPFC) regions, which additionally revealed associations with the follow-up remission status. CONCLUSIONS: Results provide initial evidence that neural pre-treatment CS+/CS- differences may hold predictive information regarding outcomes of behavioral exposure. Our findings highlight a key role of neural responses to safety cues with potentially inhibitory effects on affect-generating structures during fear conditioning.

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YNIMG Journal 2021 Journal Article

Neural adaptation of cingulate and insular activity during delayed fear extinction: A replicable pattern across assessment sites and repeated measurements

Isabelle C. Ridderbusch
Adrian Wroblewski
Yunbo Yang
Jan Richter
Maike Hollandt
Alfons O. Hamm
Hans-Ulrich Wittchen
Andreas Ströhle

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unconditioned stimulus, US). Although extinction training is well investigated, evidence regarding process-related changes in neural activation over time is still missing. Using optimized delayed extinction training in a multicentric trial we tested whether: 1) extinction training elicited decreasing CS-specific neural activation and subjective ratings, 2) extinguished conditioned fear would return after presentation of the US (reinstatement), and 3) results are comparable across different assessment sites and repeated measures. We included 100 healthy subjects (measured twice, 13-week-interval) from six sites. 24 h after fear acquisition training, extinction training, including a reinstatement test, was applied during fMRI. Alongside, participants had to rate subjective US-expectancy, arousal and valence. In the course of the extinction training, we found decreasing neural activation in the insula and cingulate cortex as well as decreasing US-expectancy, arousal and negative valence towards CS+. Re-exposure to the US after extinction training was associated with a temporary increase in neural activation in the anterior cingulate cortex (exploratory analysis) and changes in US-expectancy and arousal ratings. While ICCs-values were low, findings from small groups suggest highly consistent effects across time-points and sites. Therefore, this delayed extinction fMRI-paradigm provides a solid basis for the investigation of differences in neural fear-related mechanisms as a function of anxiety-pathology and exposure-based treatment.

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YNICL Journal 2019 Journal Article

Association of NPSR1 gene variation and neural activity in patients with panic disorder and agoraphobia and healthy controls

Johanna Gechter
Carolin Liebscher
Maximilian J. Geiger
André Wittmann
Florian Schlagenhauf
Ulrike Lueken
Hans-Ulrich Wittchen
Bettina Pfleiderer

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

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YNICL Journal 2019 Journal Article

Phasic amygdala and BNST activation during the anticipation of temporally unpredictable social observation in social anxiety disorder patients

Benedikt Figel
Leonie Brinkmann
Christine Buff
Carina Y. Heitmann
David Hofmann
Maximilian Bruchmann
Michael P.I. Becker
Martin J. Herrmann

Anticipation of potentially threatening social situations is a key process in social anxiety disorder (SAD). In other anxiety disorders, recent research of neural correlates of anticipation of temporally unpredictable threat suggests a temporally dissociable involvement of amygdala and bed nucleus of the stria terminalis (BNST) with phasic amygdala responses and sustained BNST activation. However, the temporal profile of amygdala and BNST responses during temporal unpredictability of threat has not been investigated in patients suffering from SAD. We used functional magnetic resonance imaging (fMRI) to investigate neural activation in the central nucleus of the amygdala (CeA) and the BNST during anticipation of temporally unpredictable aversive (video camera observation) relative to neutral (no camera observation) events in SAD patients compared to healthy controls (HC). For the analysis of fMRI data, we applied two regressors (phasic/sustained) within the same model to detect temporally dissociable brain responses. The aversive condition induced increased anxiety in patients compared to HC. SAD patients compared to HC showed increased phasic activation in the CeA and the BNST for anticipation of aversive relative to neutral events. SAD patients as well as HC showed sustained activity alterations in the BNST for aversive relative to neutral anticipation. No differential activity during sustained threat anticipation in SAD patients compared to HC was found. Taken together, our study reveals both CeA and BNST involvement during threat anticipation in SAD patients. The present results point towards potentially SAD-specific threat processing marked by elevated phasic but not sustained CeA and BNST responses when compared to HC.

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YNIMG Journal 2018 Journal Article

Inter-individual differences in trait anxiety shape the functional connectivity between the bed nucleus of the stria terminalis and the amygdala during brief threat processing

Leonie Brinkmann
Christine Buff
Katharina Feldker
Paula Neumeister
Carina Y. Heitmann
David Hofmann
Maximilian Bruchmann
Martin J. Herrmann

An influential framework suggests that the central nucleus of the amygdala (CeA) is involved in phasic responses to threat, while the bed nucleus of the stria terminalis (BNST) mediates sustained anxiety. However, this model has been questioned, proposing that the role of the BNST is not limited to sustained threat contexts. Rather, amygdala and BNST also seem to work in concert in the processing of discrete and briefly presented threat-related stimuli, likely dependent on inter-individual differences in anxiety. A direct test of this assumption with sufficient experimental power is missing in human research and the degree to which individual differences in trait anxiety moderate phasic responses and functional connectivity of amygdala and BNST during threat processing remains unclear. The current event-related functional magnetic resonance imaging (fMRI) study investigated activation and connectivity of amygdala and BNST, as well as modulating effects of trait anxiety, during processing of briefly presented threat-related relative to neutral standardized pictures in 93 psychiatrically healthy individuals. Both amygdala and BNST activation was increased during presentation of threat-related relative to neutral pictures. Furthermore, functional connectivity between BNST and amygdala in response to threat was positively associated with trait anxiety. These findings suggest that amygdala and BNST form a functional unit during phasic threat processing whereby their connectivity is shaped by inter-individual differences in trait anxiety.

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YNICL Journal 2017 Journal Article

Initial and sustained brain responses to threat anticipation in blood-injection-injury phobia

Leonie Brinkmann
Hendrik Poller
Martin J. Herrmann
Wolfgang Miltner
Thomas Straube

Blood-injection-injury (BII) phobia differs from other subtypes of specific phobia in that it is associated with elevated disgust-sensitivity as well as specific autonomic and brain responses during processing of phobia-relevant stimuli. To what extent these features play a role already during threat anticipation is unclear. In the current fMRI experiment, 16 female BII phobics and 16 female healthy controls anticipated the presentation of phobia-specific and neutral pictures. On the behavioral level, anxiety dominated the anticipatory period in BII phobics relative to controls, while both anxiety and disgust were elevated during picture presentation. By applying two different models for the analysis of brain responses to anticipation of phobia-specific versus neutral stimuli, we found initial and sustained increases of activation in anterior cingulate cortex (ACC), insula, lateral and medial prefrontal cortex (PFC), thalamus and visual areas, as well as initial activation in the amygdala for BII phobics as compared to healthy controls. These results suggest that BII phobia is characterized by activation of a typical neural defense network during threat anticipation, with anxiety as the predominant emotion.

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YNIMG Journal 2014 Journal Article

Activation during the Trail Making Test measured with functional near-infrared spectroscopy in healthy elderly subjects

Katja Hagen
Ann-Christine Ehlis
Florian B. Haeussinger
Sebastian Heinzel
Thomas Dresler
Laura D. Mueller
Martin J. Herrmann
Andreas J. Fallgatter

Cognitive decline is very common in age and particularly in subjects with neurodegenerative conditions. Besides memory and language, executive functions are very often affected in elderly and patients with Alzheimer's disease or Parkinson's disease. However, the neural alterations associated with these executive deficits are still not fully understood. Therefore, we measured cortical activation using functional near-infrared spectroscopy (fNIRS) in 16 healthy elderly subjects (50–75years) performing the Trail Making Test (TMT), a widely used neuropsychological instrument measuring executive function. In line with previous studies focusing on younger subjects, the results showed frontal activation during the TMT A and the TMT B in the dorsolateral prefrontal cortex, the frontopolar area and also Broca's area. Furthermore, significant activation in the left motor, somatosensory cortices and somatosensory association cortices was demonstrated. Additionally, after a median split the differences between younger (<58years) and older (>58years) subjects were analyzed with the older subjects showing a less focused prefrontal activation. Altogether, fNIRS was found to be suitable to detect cortical activation in elderly subjects during performance of the TMT as well as aging-related differences in prefrontal activation topography. These neural correlates of executive functions should be further investigated as a potential prodromal neural marker of executive deficits and neurodegenerative processes.

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YNIMG Journal 2014 Journal Article

Implicit emotion regulation in the presence of threat: Neural and autonomic correlates

Sara V. Tupak
Thomas Dresler
Anne Guhn
Ann-Christine Ehlis
Andreas J. Fallgatter
Paul Pauli
Martin J. Herrmann

Efficient emotion regulation is essential for social interaction and functioning in human society and often happens without direct intention and conscious awareness. Cognitive labeling of stimuli based on certain characteristics has been assumed to represent an effective strategy of implicit emotional regulation whereas processing based on simple perceptual characteristics (e. g. , matching) has not. Evidence exists that the ventrolateral prefrontal cortex (VLPFC) might be of functional relevance during labeling by down-regulating limbic activity in the presence of threatening stimuli. However, it remained unclear whether this VLPFC activation was particularly specific to threat because previous studies focused exclusively on threatening stimuli. In the current study, 35 healthy participants labeled or matched both threatening and neutral pictures while undergoing 52-channel functional near-infrared spectroscopy. Results showed increased VLPFC activation during labeling of threatening but not neutral pictures. No increase in prefrontal activation was detected during matching. Moreover, skin conductance increased equally for both valence conditions during initial phases of labeling whereas during matching stronger increases were found for threatening stimuli. Although a general inverse relationship between VLPFC function and skin conductance was not confirmed, both were negatively correlated during matching of threatening pictures in subjects with high state anxiety. It was concluded that the VLPFC plays an essential role during implicit emotion regulation. Further, even simple perceptual processing seems to engage regulatory top-down activation in anxious individuals.

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YNIMG Journal 2014 Journal Article

Occipital and orbitofrontal hemodynamics during naturally paced reading: An fNIRS study

Markus J. Hofmann
Michael Dambacher
Arthur M. Jacobs
Reinhold Kliegl
Ralph Radach
Lars Kuchinke
Michael M. Plichta
Andreas J. Fallgatter

Humans typically read at incredibly fast rates, because they predict likely occurring words from a given context. Here, we used functional near-infrared spectroscopy (fNIRS) to track the ultra-rapid hemodynamic responses of words presented every 280ms in a naturally paced sentence context. We found a lower occipital deoxygenation to unpredictable than to predictable words. The greater hemodynamic responses to unexpected words suggest that the visual features of expected words have been pre-activated previous to stimulus presentation. Second, we tested opposing theoretical proposals about the role of the medial orbitofrontal cortex (OFC): Either OFC may respond to the breach of expectation; or OFC is activated when the present stimulus matches the prediction. A significant interaction between word frequency and predictability indicated OFC responses to breaches of expectation for low- but not for high-frequency words: OFC is sensitive to both, bottom-up processing as mediated by word frequency, as well as top-down predictions. Particularly, when a rare word is unpredictable, OFC becomes active. Finally, we discuss how a high temporal resolution can help future studies to disentangle the hemodynamic responses of single trials in such an ultra-rapid event succession as naturally paced reading.

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YNIMG Journal 2013 Journal Article

Neuropeptide S receptor gene: Fear-specific modulations of prefrontal activation

Sara V. Tupak
Andreas Reif
Paul Pauli
Thomas Dresler
Martin J. Herrmann
Katharina Domschke
Clara Jochum
Elisabeth Haas

Since central administration of neuropeptide S (NPS) has been shown to exert anxiolytic effects on rodent behavior in a number of studies, genetic variants of its cognate G-protein coupled receptor (NPSR1) became the focus of several recent human studies on anxiety and anxiety disorders. The T allele of rs324981, which goes along with enhanced receptor function, was associated with panic disorder, increased anxiety sensitivity in healthy subjects, attenuated prefrontal brain activation and elevated amygdala responses to fear-relevant stimuli. To investigate whether prefrontal attenuations in rs324981 T allele carriers are specific to fear-relevant stimulus content and cannot be attributed to a generally higher interference of emotional stimuli, 92 subjects performed a combined cognitive and emotional Stroop task while oxygenation changes in the prefrontal cortex were recorded using functional near-infrared spectroscopy. Results showed a specific NPSR1 gene activation modulation in response to fear-relevant word stimuli. Only A-homozygotes displayed an emotional Stroop effect in terms of increased activation to fear-relevant stimuli in medial and dorsolateral prefrontal cortex. Specifically, activation in the fear-relevant condition was higher in A-homozygotes as compared to T allele carriers while no group differences were found during neutral, congruent or highly interfering incongruent color word presentation. The current results are in line with earlier imaging genetic studies and suggest a potential protective function of the NPSR1 rs324981 A/A genotype against pathologically enhanced anxiety that might be explained by stronger reflective prefrontal regulation over the subcortical fear response.

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YNIMG Journal 2011 Journal Article

NOS1 ex1f-VNTR polymorphism influences prefrontal brain oxygenation during a working memory task

Juliane Kopf
Martin Schecklmann
Tim Hahn
Thomas Dresler
Alica C. Dieler
Martin J. Herrmann
Andreas J. Fallgatter
Andreas Reif

Nitric oxide (NO) synthase produces NO, which serves as first and second messenger in neurons, where the protein is encoded by the NOS1 gene. A functional variable number of tandem repeats (VNTR) polymorphism in the promoter region of the alternative first exon 1f of NOS1 is associated with various functions of human behavior, for example increased impulsivity, while another, non-functional variant was linked to decreased verbal working memory and a heightened risk for schizophrenia. We therefore investigated the influence of NOS1 ex 1f-VNTR on working memory function as reflected by both behavioral measures and prefrontal oxygenation. We hypothesized that homozygous short allele carriers exhibit altered brain oxygenation in task-related areas, namely the dorsolateral and ventrolateral prefrontal cortex and the parietal cortex. To this end, 56 healthy subjects were stratified into a homozygous long allele group and a homozygous short allele group comparable for age, sex and intelligence. All subjects completed a letter n-back task (one-, two-, and three-back), while concentration changes of oxygenated (O2Hb) hemoglobin in the prefrontal cortex were measured with functional near-infrared spectroscopy (fNIRS). We found load-associated O2Hb increases in the prefrontal and parts of the parietal cortex. Significant load-associated oxygenation differences between the two genotype groups could be shown for the dorsolateral prefrontal cortex and the parietal cortex. Specifically, short allele carriers showed a significantly larger increase in oxygenation in all three n-back tasks. This suggests a potential compensatory mechanism, with task-related brain regions being more active in short allele carriers to compensate for reduced NOS1 expression.

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YNIMG Journal 2008 Journal Article

Differential activation of frontal and parietal regions during visual word recognition: An optical topography study

Markus J. Hofmann
Martin J. Herrmann
Ippeita Dan
Hellmuth Obrig
Markus Conrad
Lars Kuchinke
Arthur M. Jacobs
Andreas J. Fallgatter

The present study examined cortical oxygenation changes during lexical decision on words and pseudowords using functional Near-Infrared Spectroscopy (fNIRS). Focal hyperoxygenation as an indicator of functional activation was compared over three target areas over the left hemisphere. A 52-channel Hitachi ETG-4000 was used covering the superior frontal gyrus (SFG), the left inferior parietal gyrus (IPG) and the left inferior frontal gyrus (IFG). To allow for anatomical inference a recently developed probabilistic mapping method was used to determine the most likely anatomic locations of the changes in cortical activation [Tsuzuki, D. , Jurcak, V. , Singh, A. K. , Okamoto, M. , Watanabe, E. , Dan, I. , 2007. Virtual spatial registration of stand-alone fNIRS data to MNI space. NeuroImage 43 (4), 1506–1518. Subjects made lexical decisions on 50 low and 50 high frequency words and 100 pseudowords. With respect to the lexicality effect, words elicited a larger focal hyperoxygenation in comparison to pseudowords in two regions identified as the SFG and left IPG. The SFG activation difference was interpreted to reflect decision-related mechanisms according to the Multiple Read-Out Model [Grainger, J. , Jacobs, A. M. , 1996. Orthographic processing in visual word recognition: A multiple read-out model. Psychological Review 103, 518–565]. The greater oxygenation response to words in the left IPG suggests that this region connects orthographic, phonological and semantic representations. A decrease of deoxygenated hemoglobin was observed to low frequency in comparison to high frequency words in a region identified as IFG. This region’s sensitivity to word frequency suggests its involvement in grapheme–phoneme conversion, or its role during the selection of pre-activated semantic candidates.

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