Biology subjects

Merz, C. J.

Publications and source records attributed to Merz, C. J..

11 recordsLinked to original sources

bioRxiv2026

Distinct and overlapping correlates of fear acquisition and extinction across different neuroimaging modalities

Interindividual differences in fear acquisition and extinction have been related to variation in specific brain correlates. However, variability in experimental setups complicates the integration of findings. Here, we present a combined fear acquisition (n = 101) and extinction (n = 88) study from which we obtained distinct microstructural, macrostructural, and connectivity brain properties with magnetic resonance imaging in healthy, young participants. The properties included regional brain volume, cortical surface area and thickness, neurite density and orientation dispersion, and nodal efficiency of structural and functional connectivity. Fear responses were quantified as changes in skin conductance. Data from 360 cortical and 16 subcortical brain regions as well as the efficiency of network connections between them were used as independent variables in bootstrapped and cross-validated regularized regression models. Results show that numerous brain regions, spanning the so-called 'fear and extinction network' and extending beyond it, contribute to fear acquisition, to extinction, or dynamically shift between both phases. For several brain regions, data from multiple imaging modalities showed a high degree of concordance for several brain regions. These findings call for further research to examine the potential interplay between brain correlates shaping fear acquisition and extinction, as opposed to studying the imaging modalities in isolation.

neuroscience↗

bioRxiv2026

BOLD signals of learning dynamics across and within trials beyond the classical fear and extinction network

Human functional magnetic resonance imaging studies of fear conditioning often average neural responses across trials, potentially obscuring transient activations that vary across learning. In this study with 139 participants, we examined finer temporal dynamics of conditioned responding by analyzing three 2s segments within the conditioned stimulus (CS) presentation period across each quarter of fear acquisition and extinction training. This approach revealed distinct, time-specific engagement of regions within fear- and safety-related networks, both within and across trials. In particular, different activation patterns emerged across the three trial segments during CS presentation, indicating that neural responses were not limited to CS onset. We observed a more classical activation pattern at 0s relative to CS onset that diverged in later trial segments, most notably involving the amygdala, hippocampus, and prefrontal cortex (PFC) structures such as vmPFC present exclusively in 2s and 4s trial segments. We also found sustained activations consistent across all blocks of trials, such as right vlPFC activation 4s after CS onset across all fear acquisition quarters. These findings suggest that conditioned fear and safety processing unfold as dynamic spatiotemporal cascades and highlight the importance of modeling later responses following CS onset rather than focusing exclusively on onset-related activation.

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bioRxiv2025

Predicting individual differences of fear and cognitive learning and extinction

The abilities to acquire new information and to modify previously learned knowledge are critical in an ever-changing world. However, the efficacy of learning is notably variable among individuals, with extinction learning being the epitome of such variability. Abundant studies have identified a core network of brain regions including amygdala, hippocampus, dorsal anterior cingulate cortex (ACC), ventromedial prefrontal cortex (PFC) and, more recently, the cerebellum, as key players in learning and extinction. Yet, the precise interactions within this network and their relationship to individual learning abilities and extinction have remained largely unexplored. In the present study, we examined how functional (FC), effective (EC), and structural (SC) connectivity patterns in the core learning network allow predicting individual differences in the efficacy of learning, extinction, and renewal. Analysing a large dataset of over 500 participants across a multitude of paradigms, our results revealed that FC predicted better acquisition, with a central role of ACC and hippocampus, whereas SC, involving ACC and amygdala, predicted higher levels of extinction learning. EC results suggested a predominantly inhibitory coupling among core learning network nodes, with paradigm-specific EC connectivity patterns predicting learning. Our predictions not only generalised between fear and cognitive predictive learning paradigms but were also successful in predicting learning from task-related FC and simulated data. Together, these results describe the multimodal neural determinants of learning, extinction, and renewal, and may inform individualised interventions for affective disorders based on neural connectivity patterns.

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bioRxiv2025

Dopaminergic drugs modulate fear extinction related processes in humans, but effects are mild

The ability to extinguish learned fear responses is crucial for adaptive behavior. The mesolimbic dopaminergic system originating in the ventral tegmental area has been proposed to contribute to fear extinction learning because of its critical role in reward learning. The unexpected omission of aversive unconditioned stimuli (US) is considered as rewarding (outcome better than expected) and to drive extinction learning. We tested the hypothesis that extinction learning is facilitated by dopaminergic drugs and impeded by anti-dopaminergic drugs. The effects of dopamine agonists [levodopa (100 mg) and bromocriptine (1.25 mg)] and antagonists [tiapride (100 mg) and haloperidol (3 mg)] on fear extinction learning were compared to placebo in 146 young and healthy human participants. A three-day differential fear conditioning paradigm was performed with pupil size and skin conductance responses (SCRs) being recorded. Fear acquisition training was performed on day 1, extinction training on day 2, and recall was tested on day 3. The conditioned stimuli (CS+, CS-) consisted of two geometric figures. A short electrical stimulation was used as the aversive US. One of the four drugs or placebo was administered prior to the extinction phase on day 2. Overall, effects were small and seen only in the bromocriptine group. In line with our hypothesis, we measured reduced pupil dilation during late recall in the bromocriptine group compared to the placebo group, indicating faster re-extinction of spontaneously recovered fear reactions on the third day. Effects of levodopa and haloperidol were unspecific and related to generally increased SCR levels in the levodopa group (already prior to drug intake), and miotic side-effects of haloperidol. Findings provide additional support that the dopaminergic system contributes to extinction learning in humans, possibly by improving consolidation of fear extinction memory.

neuroscience↗

bioRxiv2025

Multi-modal brain properties are associated with interindividual differences in fear acquisition and extinction

Interindividual differences in fear acquisition and extinction have been related to variation in specific brain correlates. However, variability in experimental setups complicates the integration of findings. Here, we present a combined fear acquisition (n = 101) and extinction (n = 88) experiment in which both phenomena were related to brain correlates obtained via functional magnetic resonance imaging in healthy, young participants. Correlates included regional brain volume, cortical surface area and thickness, neurite density and orientation dispersion, structural and functional connectivity. Fear responses were quantified as changes in skin conductance. Data from 376 brain areas and 70,500 network connections were used as independent variables in regularized regression models. Regression models of fear acquisition could be obtained for all modalities but regional brain volume. There were 284 predictors of which 77 appeared in exactly two models and 19 in exactly three. The latter primarily included brain areas from the somatosensory, insular, cingulate, and frontal cortices. Fear extinction yielded regression models based on neurite density, structural connectivity, and functional connectivity with 112 predictors in total. Two predictors, located in the dorsolateral prefrontal cortex, replicated across exactly two regression models (neurite density and structural connectivity). This study is the first to investigate the neural correlates of both fear acquisition and extinction in an explorative, multi-modal fMRI approach. Results show that numerous brain regions contribute to fear conditioning, some of them via more than one correlate. These findings call for further research to examine the potential interplay between brain correlates shaping fear conditioning.

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bioRxiv2025

The relationship between cortisol, grid-like representations and path integration

Acute stress triggers the release of cortisol, which broadly affects cognitive processes. Path integration, a specific navigational process, relies heavily on grid cells in the entorhinal cortex (EC). The EC contains glucocorticoid receptors and is therefore likely to be influenced by cortisol, though little is known about this relationship. Given the role of the EC in neurological diseases such as Alzheimers Disease, investigating the effects of cortisol on this brain region may offer insights into how stress affects these diseases. In this study, we examined the effects of cortisol on human path integration in thirty-nine healthy participants across two sessions. On each day, they received either 20mg cortisol or a placebo and performed a virtual homing task during functional magnetic resonance imaging (fMRI). Cortisol markedly impaired path integration performance, independent of path distance or the presence of spatial cues. Additionally, cortisol altered navigational strategies, leading participants to navigate further away from landmarks, which was associated with worse performance. FMRI results showed that cortisol increased the activation of right caudate nucleus in the presence of landmarks. Using a representational similarity analysis, we observed grid-like representations in the right posterior-medial EC specifically on day one under placebo, but these were diminished by cortisol. Grid-like representations facilitated performance over short distances but hindered it over longer ones, suggesting that grid cells support PI specifically in case of short trajectories. Overall, the study indicates that cortisol-induced disruption in grid cell function in the EC may underly stress effects on path integration.

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bioRxiv2025

Cerebellar transcranial alternating current stimulation in the theta band facilitates extinction of learned fear responses

Fear extinction is a major component of exposure therapy for anxiety disorders. There is initial evidence that the cerebellum contributes to fear extinction learning, i.e., the ability to learn that certain stimuli are no longer associated with an aversive outcome. So far, however, knowledge of the cerebellums role in extinction is scarce. In the present study, 6 Hz cerebellar transcranial alternating current stimulation (ctACS) was used to modulate cerebellar function during extinction learning in young and healthy human participants in an MRI study. A two- day differential fear conditioning paradigm was used with acquisition and extinction training being performed on day 1, and fear extinction recall being tested on day 2. 6 Hz ctACS reduced spontaneous recovery of the initial fear association during recall, stabilizing extinction effects compared to sham ctACS. fMRI data during recall revealed significantly reduced activation in cortical areas involved in initial fear acquisition, such as the anterior cingulate and insula, in the verum ctACS group compared to the sham group. During extinction training, on the other hand, the verum group exhibited more widespread cerebral activation compared to the sham group. Group differences were significant in occipital cortical areas. Although direct stimulation effects cannot be excluded, increased activation in the visual cortex may reflect enhanced encoding and processing of visual information during fear extinction learning. The findings suggest that theta-range oscillatory interactions between the cerebellum and cortical areas support extinction processes and provide causal evidence of the cerebellar role in the human fear extinction network. Significance StatementWhile the cerebellum is well known for its role in associative learning, its contribution to fear extinction learning remains underexplored. This study used 6 Hz cerebellar transcranial alternating current stimulation (ctACS) to modulate cerebellar function during extinction training in healthy participants. The present data demonstrate that ctACS enhances cerebral cortical activation during extinction training which is followed by enhanced recall of the extinction memory and subsequently reduced activation of cerebral cortical areas associated to spontaneous recovery of fear memory. These findings provide causal evidence for the cerebelluar involvement in the human fear extinction network and suggest that enhancing cerebellar theta oscillations may be useful to support exposure therapy.

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bioRxiv2024

Human cerebellum and ventral tegmental area interact during extinction of learned fear

The key elements for fear extinction learning are unexpected omissions of expected aversive events, which are considered to be rewarding. Given its reception of reward information, we tested the hypothesis that the cerebellum contributes to reward-like prediction error processing driving extinction learning via its connections with the ventral tegmental area (VTA). Forty-three young and healthy participants performed a three-day fear conditioning paradigm in a 7T MR scanner. The cerebellum and VTA were active during unexpected omissions of aversive unconditioned stimuli in the initial extinction trials and in other learning phases, in line with the proposed role of prediction-error processing. Increased functional connectivity was observed between the cerebellum and VTA, indicating that they are functionally coupled during fear extinction learning. These results suggest that an interaction between the cerebellum and VTA should be incorporated into the existing model of the fear extinction network.

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bioRxiv2020

Conditioned fear reactions are associated with gray matter density but not cortical microstructure

Research has shown that fear acquisition, in reaction to potentially harmful stimuli or situations, is characterized by pronounced interindividual differences. It is likely that such differences are evoked by variability in the macro- and microstructural properties of brain regions involved in the processing of threat or safety signals from the environment. Indeed, previous studies have shown that the strength of conditioned fear reactions is associated with the cortical thickness or volume of various brain regions. However, respective studies were exclusively targeted at single brain regions instead of whole brain networks. Here, we tested 60 young and healthy individuals in a differential fear conditioning paradigm while they underwent fMRI scanning. In addition, we acquired T1-weighted and multi-shell diffusion-weighted images prior to testing. We used task-based fMRI data to define global brain networks which exhibited increased BOLD responses towards CS+ or CS- presentations, respectively. From these networks, we obtained mean values of gray matter density, neurite density, and neurite orientation dispersion. We found that mean gray matter density averaged across the CS+ network was significantly correlated with the strength of conditioned fear reactions quantified via skin conductance response. Measures of neurite architecture were not associated with conditioned fear reaction in any of the two networks. Our results extend previous findings on the relationship between brain morphometry and fear learning. Most importantly, our study is the first to introduce neurite imaging to fear learning research and discusses how its implementation can be improved in future research.

neuroscience↗

bioRxiv2020

Fear learning sculpts functional brain connectivity at rest beyond the traditional fear network in humans

Neuroscientific research has identified specific brain networks involved in the acquisition of fear memories. Using fMRI to assess changes in resting-state functional connectivity (RSFC) induced by fear acquisition, single brain regions from these networks have also been linked to fear memory consolidation. However, previous studies only examined RSFC changes within restricted sets of brain regions or without a proper control group, leaving our knowledge about fear consolidation outside of traditional fear networks incomplete. Here, we tested a group of 84 healthy participants in a differential fear conditioning paradigm and quantified RSFC changes between 358 cortical and 16 subcortical brain areas. Subsequent to fear learning, 21 functional connections exhibited significant RSFC changes. Importantly, these connections were not restricted to the traditional fear networks but also comprised various frontal and visual areas. Our findings indicate that fear memory consolidation is a complex process that integrates relevant information across the entire brain.

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bioRxiv2019

The cerebellum is involved in processing of predictions and prediction errors in a fear conditioning paradigm

Prediction errors are thought to drive associative fear learning. Surprisingly little is known about the possible contribution of the cerebellum. To address this question, healthy participants underwent a differential fear conditioning paradigm during 7T magnetic resonance imaging. An event-related design allowed us to separate cerebellar fMRI signals related to the visual conditioned stimulus (CS) from signals related to the subsequent unconditioned stimulus (US; an aversive electric shock). We found significant activation of cerebellar lobules Crus I and VI bilaterally related to the CS+ compared to the CS-. Most importantly, significant activation of lobules Crus I and VI was also present during the unexpected omission of the US in unreinforced CS+ acquisition trials. This activation disappeared during extinction when US omission became expected. These findings provide evidence that the cerebellum has to be added to the neural network processing predictions and prediction errors in the emotional domain.

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