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Büchel, C.

Publications and source records attributed to Büchel, C..

17 recordsLinked to original sources
bioRxiv2026

Withdrawal latency in a human hot plate analog tracks inter-individual differences in pain sensitivity

Pain research relies mainly on self-report in humans and nocifensive behavior in animals. This asymmetry limits cross-species translation and neglects movement as integral to human pain responses. We therefore developed a human analog of the rodent hot plate test and tested whether temporal and kinematic features of nocifensive withdrawal can capture inter-individual differences in pain sensitivity. Ninety-one healthy participants rested their forearm on a thermode that rapidly heated to and held a fixed noxious temperature (46 {degrees}C or 48 {degrees}C) and were instructed to withdraw once the percept reached their pain threshold or tolerance. From wrist accelerometry, we extracted withdrawal latency and peak acceleration, an index of withdrawal vigor, and related both to pain intensity ratings from a separate, temperature-matched task and to calibrated pain sensitivity. Participants withdrew earlier and with higher peak acceleration at 48 {degrees}C than at 46 {degrees}C. Crucially, withdrawal latency tracked inter-individual differences in pain sensitivity: Participants who withdrew earlier reported higher pain in the separate task (48 {degrees}C: r = -.47 and -.50) and showed lower pain thresholds and higher suprathreshold sensitivity during calibration. In contrast, withdrawal vigor showed no such relationship, despite high reliability. Withdrawal latency can thus serve as a behavioral readout of inter-individual differences in pain sensitivity, whereas vigor might reflect intra-individual motor scaling with stimulus intensity. By separating the decision to withdraw from its motor execution, this paradigm offers a behavioral complement to traditional self-report and provides a translational link between human and preclinical pain assays.

neuroscience↗
bioRxiv2026

The pursuit of motivational goals reduces pain through an opioidergic mechanism

Pain promotes protective behavior but can interfere with other biologically important goals. Survival may require overcoming pain to obtain rewards, secure resources or escape danger, yet evidence for pain modulation by competing demands and endogenous modulatory systems during goal pursuit is lacking. We developed a paradigm in which participants chose whether to pursue monetary rewards despite painful heat stimulation during fMRI, under placebo or opioid receptor blockade with naloxone. Actively pursuing motivational goals during painful stimulation reduced perceived pain and increased fMRI signal in pain-modulatory cortical regions, including multiple subregions of the rostral anterior cingulate cortex (rACC) and dorsolateral prefrontal cortex, alongside enhanced rACC-periaqueductal gray coupling, consistent with recruitment of the descending pain modulatory system. Behavioral and neural effects were attenuated by naloxone, supporting a mediating role for endogenous opioids. These findings provide convergent evidence that active goal pursuit engages opioidergic pain modulatory mechanisms to reduce pain in humans.

neuroscience↗
bioRxiv2026

Opposing BOLD signals and oxygen metabolism largely arise from statistical uncertainty in metabolic estimates

Recent work by Epp et al. (2025) reported widespread voxel-wise sign discordance between task-evoked blood-oxygenation-level-dependent (BOLD) responses and estimated changes in cerebral metabolic rate of oxygen ({Delta}CMRO2), raising important questions about the interpretability of BOLD functional magnetic resonance imaging. Reanalysing the dataset, we found that {Delta}CMRO2 estimates showed substantial voxel-wise variability across participants, consistent with the noise sensitivity of model-based metabolic estimates. When this variability was taken into account, 77.2% of voxels could not be robustly classified, as {Delta}CMRO2 effects lacked sufficient statistical support to determine concordance or discordance. Where classification was possible, positive BOLD responses were predominantly concordant with metabolism, whereas discordance was considerably higher for negative BOLD responses. These findings suggest that the observed BOLD-metabolism discordance reported previously largely reflects statistical uncertainty in CMRO2 estimates rather than widespread physiological sign reversal.

neuroscience↗
bioRxiv2025

Exercise-Induced Hypoalgesia Following High- vs. Low-Intensity Aerobic Exercise in Fit Females

In a previous study by our group (Nold et al., 2025), we investigated exercise-induced pain modulation after high-intensity compared to low-intensity exercise in a heterogeneous sample of diverse fitness levels. Exploratory analyses suggested an interaction of sex, fitness level, and drug treatment, indicating that males showed increasing hypoalgesia after high- compared to low-intensity exercise with increasing fitness levels, which was diminished when naloxone was administered. In contrast, these effects were not evident in females. These exploratory findings warranted further investigation to determine if and to what extent exercise-induced pain modulation depends on fitness level and/or sex. In this current study, we investigated an all-female sample (N = 21) of high fitness levels using a similar paradigm as in the previous study, comparing heat and pressure pain ratings after high-intensity and low-intensity exercise. Our data show an interaction of exercise intensity and stimulus intensity in heat pain, with greater pain relief following high-intensity exercise, especially at the highest stimulus intensity. Despite results for pressure pain not reaching significance, a similar trend was evident. These results suggest that females at a high fitness level also show exercise-induced pain modulation for high-intensity compared to low-intensity exercise. Furthermore, we pooled the data of the current and previous study, providing evidence for fitness level but not sex to moderate exercise-induced pain modulation in heat pain. These findings suggest that exercise-induced pain modulation depends on fitness level but not on sex.

physiology↗
bioRxiv2023

Brainstem arousal systems adaptively shape large-scale cortical interactions for flexible decision-making

Most perceptual decisions entail a flexible mapping from sensory input to motor output. Flexible input-output mapping is reflected in correlated variability within the cortical network involved in perceptual decisions. Here, we tested the idea that brainstem arousal systems are involved in flexible input-output mapping and changes in cortical correlated variability. We combined brainstem fMRI, pupillometry, and time-resolved assessment of the intrinsic correlations between cortical population codes for stimulus and action. Human participants reported the orientation of visual stimuli by button presses, while the required stimulus-response mapping rule could undergo hidden and unpredictable changes. Rule switches evoked brainstem and pupil responses as well as changes in computational model-inferred, latent variables. These variables governed participants rule-switching behavior and pupil responses. Brainstem activity and pupil dilation preceded increases in the strength of correlations between cortical stimulus and action codes. Brainstem arousal systems may promote the reorganization of sensorimotor cortical pathways for flexible decisions.

neuroscience↗
bioRxiv2023

Conditioned pain modulation of pressure pain is associated with reduced activation in the parietal operculum and posterior insula

Conditioned pain modulation (CPM) is the phenomenon of pain inhibiting further pain. CPM is impaired in patients suffering from various chronic pain conditions and may resemble a pro-nociceptive profile. A possible neural mechanism for CPM is descending control from cortical regions via brainstem that modulates neural activity at the level of the dorsal horn of the spinal cord where noxious input first arrives. We studied the involvement of the descending pain modulatory pathway by simultaneous functional imaging of the brain, brainstem, rostral medulla, and cervical spinal cord during CPM with pressure cuff algometry in 42 healthy human participants. Subjective CPM as measured by decreased pain ratings developed over the experiment with application of repeated short test stimuli for long conditioning pain compared with non-painful conditioning. Test stimuli paired with painful conditioning were associated with decreased BOLD fMRI activity in the parietal operculum (secondary somatosensory cortex) and posterior insula, as well as increased responses in bilateral primary somatosensory cortices. Subjective CPM reflected in pain ratings was associated with decreased test stimulus responses in somatosensory and pain-responsive brain regions such as the anterior and posterior insula and the parietal operculum. Conditioning pain and test pain were associated with increased neural activity in stimulus-ipsilateral spinal cord dorsal horn at segment C6 and C4, respectively. No evidence for neural correlates of CPM or associations with subjective CPM was observed in the spinal cord. Functional connectivity between the brain and spinal cord was altered during both conditioning and test pain but did not depend on conditioning intensity. Taken together, we observed neural activity associated with both negative (CPM) and positive modulation of pain in different somatosensory and pain-associated brain regions, and an association of these and other neural responses with subjective CPM. While we found that painful stimuli altered the connectivity along the descending pain modulatory pathway, we did not find evidence for a modulation by conditioning intensity nor neural correlates of CPM in the spinal cord.

neuroscience↗
bioRxiv2023

Bridging stimulus generalization and representation learningvia rational dimensionality reduction

Generalization, the transfer of knowledge to novel situations, has been studied in distinct disciplines that focus on different aspects. Here we propose a Bayesian model that assumes an exponential mapping from psychological space to outcome probabilities. This model is applicable to probabilistic reinforcement and integrates representation learning by tracking the relevance of stimulus dimensions. Since the belief state about this mapping is dependent on prior knowledge, we designed three experiments that emphasized this aspect. In all studies, we found behavior to be influenced by prior knowledge in a way that is consistent with the model. In line with the literature on representation learning, we found the representational geometry in the middle frontal gyrus to correspond to the behavioral preference for one over the other stimulus dimension and to be updated as predicted by the model. We interpret these findings as support for a common mechanism of generalization.

neuroscience↗
bioRxiv2023

Ventral premotor cortex influences spinal cord activation during force generation

Force generation is a crucial element of dexterity and a highly relevant skill of the human motor system. How cerebral and spinal components interact and how spinal activation is influenced by cerebral primary motor and premotor areas is poorly understood. Here we conducted combined cortico-spinal functional MRI during a simple visually guided isometric force generation task in a group of 20 healthy young subjects. Activation was localized in the ipsilateral cervical spinal cord and contralateral primary motor and premotor areas. The main finding is that spinal activation was influenced by ventral premotor cortex activation. Spinal activation was furthermore significantly correlated with primary motor cortex activation while increasing target forces led to an increase in the amount of activation. These data indicate that human premotor areas such as the ventral premotor cortex might be functionally connected to the lower cervical spinal cord contributing to distal upper limb functions, a finding which extends our understanding about human motor function beyond the animal literature.

neuroscience↗
bioRxiv2022

Agency and Expectations in Pain Treatment: An Investigation of the Active Inference Model

The fact that we cannot tickle ourselves is traditionally explained by the attenuation of somatosensation by predictions from a forward model of self-generated movements. Alternatively, it has been suggested within the framework of active inference that Bayes-optimal reduction of sensory precision can explain this phenomenon. Combining a pain paradigm with stimulus-related expectations allows to compare both models through predictions from the Bayesian account of expectation-based hypoalgesia, where pain is influenced by the precisions of somatosensation and expectation. In two experiments, heat pain was sham-treated either externally or by the subject, while a cue created higher or lower treatment expectations. Both experiments revealed greater pain relief under self-treatment and high treatment expectations. Electroencephalography revealed a modulation of theta-to-beta frequencies linked to agency and top-down modulations of pain perception. Computational modeling showed that this is better explained by an attenuation of somatosensation than a downregulation of somatosensation precision, favoring the forward model.

neuroscience↗
bioRxiv2022

Pain-related learning signals in the human insula

Pain is not only a perceptual phenomenon, but also a preeminent learning signal. In reinforcement learning models, prediction errors (PEs) play a crucial role, i.e. the mismatch between expectation and sensory input. In particular, advanced learning models require the representation of different types of PEs, namely signed PEs (whether more or less pain was expected) to specify the direction of learning, and unsigned PEs (the absolute deviation from an expectation) to adapt the learning rate. The insula has been shown to play an important role in pain intensity coding and in signaling surprise. However, mainly unsigned PEs could be identified in the anterior insula. It remains an open question whether these PEs are specific to pain, and whether signed PEs are also represented in the insula. To answer these questions, 47 subjects learned associations of two conditioned stimuli (CS) with four unconditioned stimuli (US; painful heat or loud sound, of one low and one high intensity each) while undergoing functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. CS-US associations reversed multiple times between intensities and between sensory modalities, generating frequent PEs. SCRs indicated comparable nonspecific characteristics of the two modalities. fMRI analyses focusing on the insular and opercular cortices contralateral to painful stimulation showed that activation in the anterior insula correlated with unsigned intensity PEs. Importantly, this unsigned PE signal was similar for pain and aversive sounds and also modality PEs, indicating an unspecific aversive surprise signal. Conversely, signed pain intensity PE signals were modality-specific and located in the dorsal posterior insula, an area previously implicated in pain intensity processing. Previous studies have identified abnormal insula function and abnormal learning as potential causes of pain chronification. Our findings link these results and suggest one potential mechanism, namely a misrepresentation of learning relevant prediction errors in the insular cortex.

neuroscience↗
bioRxiv2022

Bicarbonate Activation of Monomeric Photosystem II-PsbS/Psb27 Complex

In thylakoid membranes, Photosystem II monomers from the stromal lamellae contain the subunits PsbS and Psb27 (PSIIm-S/27), while Photosystem II monomers from granal regions (PSIIm) lack these subunits. Here, we have isolated and characterised these two types of Photosystem II complexes. The PSIIm-S/27 showed enhanced fluorescence, the near-absence of oxygen evolution, as well as limited and slow electron transfer from QA to QB compared to the near-normal activities in the granal PSIIm. However, when bicarbonate was added to the PSIIm-S/27, water splitting and QA to QB electron transfer rates were comparable to those in granal PSIIm. The findings suggest that the binding of PsbS and/or Psb27 inhibits forward electron transfer and lowers the binding affinity for the bicarbonate. This can be rationalized in terms of the recently discovered photoprotection role played by bicarbonate binding via the redox tuning of the QA/QA*- couple, which controls the charge recombination route, and this limits chlorophyll triplet mediated 1O2 formation (Brinkert K et al. (2016) Proc Natl Acad Sci U S A. 113(43):12144-12149). These findings suggest that PSIIm-S/27 is an intermediate in the assembly of PSII in which PsbS and/or Psb27 restrict PSII activity while in transit, by using a bicarbonate-mediated switch and protective mechanism. One sentence summaryA photosystem II monomer with PsbS and Psb27 as additional subunits, is inactive as isolated but activated by bicarbonate, and is attributed to be a late-stage intermediate in photoassembly.

plant biology↗
bioRxiv2021

Alpha-to-beta- and gamma-band activity reflect predictive coding in affective visual processing

Processing of negative affective pictures typically leads to desynchronization of alpha-to-beta frequencies (ERD) and synchronization of gamma frequencies (ERS). Given that in predictive coding higher frequencies have been associated with prediction errors, while lower frequencies have been linked to expectations, we tested the hypothesis that alpha-to-beta ERD and gamma ERS induced by aversive pictures are associated with expectations and prediction errors, respectively. We recorded EEG while volunteers were involved in a probabilistically cued affective picture task using three different negative valences to produce expectations and prediction errors. Our data show that alpha-to-beta band activity was related to the expected valence of the stimulus as predicted by a cue. The absolute mismatch of the expected and actual valence, which denotes an absolute prediction error was related to gamma band activity. This demonstrates that top-down predictions and bottom-up prediction errors are represented in specific spectral patterns associated with affective picture processing.

neuroscience↗
bioRxiv2020

The temporal characteristics of expectations and prediction errors in pain

In the context of a generative model, such as predictive coding, pain and heat perception can be construed as the integration of expectation and input with their difference denoted as a prediction error. In a previous neuroimaging study (Geuter et al., 2017) we observed an important role of the insula in such a model, but could not establish its temporal aspects. Here we employed electroencephalography to investigate neural representations of predictions and prediction errors in heat and pain processing. Our data show that alpha-to-beta activity was associated with stimulus intensity expectation, followed by a negative modulation of gamma band activity by absolute prediction errors. This is in contrast to prediction errors in visual and auditory perception, which are associated with increased gamma band activity, but is in agreement with observations in working memory and word matching, which show gamma band activity for correct, rather than violated predictions.

neuroscience↗
bioRxiv2019

Neurobehavioural characterisation and stratification of reinforcement-related behaviour

AbstractReinforcement-related cognitive processes, such as reward processing, impulsiveness and emotional processing are critical components of externalising and internalising behaviours. It is unclear to what extent each of these processes contributes to individual behavioural symptoms, how their neural substrates give rise to distinct behavioural outcomes, and if neural profiles across different reinforcement-related processes might differentiate individual behaviours. We created a statistical framework that enabled us to directly compare functional brain activation during reward anticipation, motor inhibition and viewing of emotional faces in the European IMAGEN cohort of 2000 14-year-old adolescents. We observe significant correlations and modulation of reward anticipation and motor inhibition networks in hyperactivity, impulsivity, inattention and conduct symptoms, and describe neural signatures across neuroimaging tasks that differentiate these behaviours. We thus characterise shared and distinct functional brain activation patterns that underlie different externalising symptoms and identify neural stratification markers, while accounting for clinically observed co-morbidity.

neuroscience↗
bioRxiv2019

Sleep, regional grey matter volumes, and psychological functioning in adolescents

Changing sleep rhythms in adolescents often lead to sleep deficits and increased variability in sleep schedules. The adolescent brain, and in particular the rapidly developing structures involved in emotional control, are vulnerable to external and internal factors. In our previous study in adolescents at age 14, we observed a strong relationship between weekend sleep schedules and regional medial prefrontal cortex grey matter volumes. Here, we aimed to assess whether this relationship remained in this group of adolescents of the general population at the age of 16 (n=101; mean age 16.8 years; 55% girls). We further examined grey matter volumes in the hippocampi and the amygdalae, calculated with voxel-based morphometry. In addition, we investigated the relationship between regional grey matter volumes with psychological functioning. Sleep was assessed with self-reports and psychological functioning with the Strengths and Difficulties Questionnaire and tests on working memory and impulsivity. Later weekend wake-up times were associated with smaller grey matter volumes in the medial prefrontal cortex and the amygdalae, and greater weekend delays in wake-up time were associated with smaller grey matter volumes in the right hippocampus and amygdala. The medial prefrontal cortex region mediated the correlation between weekend wake up time and both externalising and internalising symptoms. Paying attention to regular sleep habits during adolescence could act as a protective factor against the emergence of psychopathology via enabling favourable brain development.

neuroscience↗
bioRxiv2019

The parietal operculum preferentially encodes heat pain and not salience

Substantial controversy exists as to which part of brain activity is genuinely attributable to pain-related percepts, and which activity is due to general aspects of sensory stimulation, such as its salience, or the accompanying arousal. The challenge posed by this question rests largely in the fact that pain per se exhibits highly intense but unspecific characteristics. These therefore should be matched by potential control conditions. Here, we used a unique combination of functional magnetic resonance imaging, behavioral and autonomic measures to address this longstanding debate in pain research.\n\nSubjects rated perceived intensity in a sequence alternating between heat and sound stimuli. Neuronal activity was monitored using fMRI. Either modality was presented in six different intensities, three of which lay above the pain threshold (for heat) or the unpleasantness threshold (for sound). We performed our analysis on 26 volunteers in which psychophysiological responses (as per skin conductance responses) did not differ between the two stimulus modalities. Having thus ascertained a comparable amount of stimulation-related but unspecific activation, we analyzed stimulus response functions after painful stimulation, and contrasted them with those of the matched acoustic control condition. Furthermore, analysis of fMRI data was performed on the brain surface to circumvent blurring issues stemming from the close proximity of several regions of interest located in heavily folded cortical areas. We focused our analyses on insular and periinsular regions which are strongly involved in processing of painful stimuli. We employed an axiomatic approach to determine areas showing higher activation in painful compared to non-painful heat, and at the same time showing a steeper stimulus response function for painful heat as compared to unpleasant sound. Intriguingly, an area in the posterior parietal operculum emerged whose response showed a pain preference after satisfying all axiomatic constraints.\n\nThis result has important implications for the interpretation of functional imaging findings in pain research, as it clearly demonstrates that there are areas whose activity following painful stimulation is not due to general attributes or results of sensory stimulation, such as salience or arousal. Conversely, several areas did not conform to the formulated axioms to rule out general factors as explanations.

neuroscience↗
bioRxiv2019

The neurofunctional basis of affective startle modulation in humans - evidence from combined facial EMG-fMRI

The startle reflex, a protective response elicited by an immediate, unexpected sensory event, is potentiated when evoked during threat and inhibited during safety. In contrast to skin conductance responses or pupil dilation, modulation of the startle reflex is valence-specific and considered the cross-species translational tool for defensive responding.\n\nRodent models implicate a modulatory pathway centering on the brainstem (i.e., nucleus reticularis pontis caudalis, PnC) and the centromedial amygdala (CeM) as key hubs for flexibly integrating valence information into differential startle magnitude.\n\nWe employed innovative combined EMG-fMRI measurements in two independent experiments and samples and provide converging evidence for the involvement of these key regions in the modulatory acoustic startle reflex pathway in humans. Furthermore, we provide the crucial direct link between EMG startle eye-blink magnitude and neural response strength.\n\nWe argue that startle-evoked amygdala responding and its affective modulation may hold promise as an important novel tool for affective neuroscience.

neuroscience↗