Biology subjects

Timmann, D.

Publications and source records attributed to Timmann, D..

16 recordsLinked to original sources

bioRxiv2026

Cerebellar activation in human placebo analgesia: Bridging findings from mice to humans

Placebo analgesia has traditionally been explained by top-down cortical regulation of brainstem and spinal pathways. Recent circuit-level work in animal models identified a rostral anterior cingulate-pontine-cerebellar pathway that contributes to expectation-based analgesia, implicating cerebellum circuits in placebo effects1. Building on these findings, we examined pontine and cerebellar contributions within a large individual-participant meta-analysis of human neuroimaging studies of placebo analgesia2 (n = 603). We found that the effects of human pain and placebo converge in cerebellar territories embedded in higher-order cognitive3,4 and action-mode networks5. These regions exhibit placebo-induced anticipatory increases and reduced responses during painful stimulation, which correlate with the magnitude of placebo analgesia, consistent with predictive configuration of the system. Pontine responses also correlate with individual differences in placebo analgesia. In independent Human Connectome Project data (n = 820), pontine activity is functionally connected with cingulate and cerebellar regions implicated in placebo analgesia. Together, these findings support a model in which expectation effects are implemented via predictive configuration of a cortico-pontine-cerebellar system.

neuroscience↗

bioRxiv2026

Cerebellar Gray Matter Volume Changes Across Development: Posterolateral and Vermal Transient Increases during Adolescence

The cerebellum undergoes substantial maturation with regionally distinct developmental trajectories. This study examined cerebellar gray matter volume (GMV) in healthy children, adolescents, and adults, using voxel-based morphometry, the ACAPULCO algorithm, and the SUIT toolbox for cerebellum-optimized analyses. A total of 104 typically developing children (n=31, 6-9 years), adolescents (n=35, 13-17 years), and adults (n=38, 30-40 years) were included. We hypothesized age group differences in cerebellar GMV, with adolescents showing the greatest volume, specifically in posterolateral regions. Results revealed significant group differences in GMV. We observed region-specific volumetric patterns, with some areas (e.g., Crus II, lobule X) increasing from childhood to adolescence followed by stabilization, whereas other areas (e.g., lobules I-IV and VI, Crus I, vermis VI and VIIb) exhibited peak GMV during adolescence, with lower volumes in both children and adults. These patterns were partly consistent with our hypothesis. Notably, no regions had greater GMV in adults than adolescents, suggesting that cerebellar growth peaks in adolescence before stabilizing. Our findings indicate differential developmental patterns both between and within lobules of the cerebellum, and highlight adolescence as a peak period of cerebellar growth, with potential implications for the development of cerebellar-supported cognitive and emotional functions that undergo significant changes during this period.

neuroscience↗

bioRxiv2026

Harmonizing the stimulation dose of focal tDCS across target sites

Non-invasive brain stimulation is an established tool for modulating neural activity that holds promise for advancing both cognitive neuroscience and clinical interventions. Focal transcranial direct current stimulation (tDCS), using center-surround electrode montages, enables more region-specific targeting. Although computational models can simulate individual electric fields, no existing approach enables the prospective individualization of electrode placement while standardizing the dose across targeted brain regions. In the current preparatory methodological study, we present a modeling-based framework that harmonizes the electric field strength between different target regions at the group level, but preserves inter-individual variability. This enables systematic examination of dose-response relationships and their regional differences. Positioning of the center-surround electrode montages is individualized to ensure focusing of the electric field on the target regions. We started by defining brain targets for eight cognitive and motor functions using MRI data from 43 participants. Using field simulations, we then estimated a group-average field strength in the target regions that had led to behavioral and physiological effects in prior tDCS studies (resulting in 0.2 V/m). The radii of the center-surround montages were optimized for each target region to achieve the intended field strength while maximizing focality. Validation in an independent sample (n=53) confirmed that the intended target field strength is achieved on average for new participants. The described computational tools are made available as open-source software, allowing other researchers to apply our individualization framework with parameters (target regions and target field strengths) tailored to their specific research questions; and are currently being implemented in a multi-center study involving approximately 1,000 datasets.

neuroscience↗

bioRxiv2025

A Core Pattern of Cerebellar and Brainstem Degeneration and Reduced Cerebrocerebellar Structural Covariance in Spinocerebellar Ataxia Type 3 (SCA3): MRI Volumetrics from ENIGMA-Ataxia

ObjectiveSpinocerebellar ataxia type 3 (SCA3) is a rare, inherited neurodegenerative disease. Here, we profile the spatial spread of atrophy across the whole brain, determine whether brain degeneration preferentially maps onto specific functional networks, and investigate the relationship between cerebellar and cerebral anatomical changes. MethodsWhole-brain grey and white matter (GM and WM) voxel-based morphometry was performed on 408 individuals with SCA3 (82 pre-ataxic) and 293 controls. The SCA3 cohort was stratified by ataxia severity to investigate disease progression, with cerebellar GM atrophy mapped onto a task-based functional atlas. Volume was correlated with disease duration and intensity. Cerebrocerebellar volumetric covariance was assessed to determine whether atrophy was coupled between infra- and supratentorial regions. ResultsThe pattern of atrophy is spatially consistent but progressive in magnitude across the disease course. The greatest atrophy was found in the pons, cerebellar WM, and cerebellar peduncles; correlations with disease severity and duration were also strongest in these regions. Cerebellar GM atrophy was greatest in functional regions associated with motor execution and planning, attention, and emotional processing. Sparse cerebral cortical atrophy appears only in the most severe disease subgroup, while striatal atrophy begins in the earliest stages. Reduced cerebrocerebellar structural covariance is observed in SCA3 participants versus controls. InterpretationWhile cerebellar and brainstem atrophy become more severe, the pattern of atrophy remains largely consistent as SCA3 progresses. Cerebellar GM degeneration occurs in regions associated with motor, cognitive, and affective control, in line with clinical presentation. Cerebellar atrophy is not directly mirrored by cerebral changes.

neuroscience↗

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.

neuroscience↗

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

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.

neuroscience↗

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.

neuroscience↗

bioRxiv2024

The Pattern and Staging of Brain Atrophy in Spinocerebellar Ataxia Type 2 (SCA2): MRI Volumetrics from ENIGMA-Ataxia

ObjectiveSpinocerebellar ataxia type 2 (SCA2) is a rare, inherited neurodegenerative disease characterised by progressive deterioration in both motor coordination and cognitive function. Atrophy of the cerebellum, brainstem, and spinal cord are core features of SCA2, however the evolution and pattern of whole-brain atrophy in SCA2 remain unclear. We undertook a multi-site, structural magnetic resonance imaging (MRI) study to comprehensively characterize the neurodegeneration profile of SCA2. MethodsVoxel-based morphometry analyses of 110 participants with SCA2 and 128 controls were undertaken to assess groupwise differences in whole-brain volume. Correlations with clinical severity and genotype, and cross-sectional profiling of atrophy patterns at different disease stages, were also performed. ResultsAtrophy in SCA2 relative to controls was greatest (Cohens d>2.5) in the cerebellar white matter (WM), middle cerebellar peduncle, pons, and corticospinal tract. Very large effects (d>1.5) were also evident in the superior cerebellar, inferior cerebellar, and cerebral peduncles. In cerebellar grey matter (GM), large effects (d>0.8) mapped to areas related to both motor coordination and cognitive tasks. Strong correlations (|r|>0.4) between volume and disease severity largely mirrored these groupwise outcomes. Stratification by disease severity showed a degeneration pattern beginning in cerebellar and pontine WM in pre-clinical subjects; spreading to the cerebellar GM and cerebro-cerebellar/corticospinal WM tracts; then finally involving the thalamus, striatum, and cortex in severe stages. InterpretationThe magnitude and pattern of brain atrophy evolves over the course of SCA2, with widespread, non-uniform involvement across the brainstem, cerebellar tracts, and cerebellar cortex; and late involvement of the cerebral cortex and striatum.

neuroscience↗

bioRxiv2024

Altered cortico-cerebellar connectivity in cerebellar degeneration patients improves with motor training

People with cerebellar degeneration show characteristic ataxic motor impairments. Despite cerebellar dysfunction, they can still improve motor performance through sensorimotor training. Yet, how such training affects functional brain networks affected by cerebellar degeneration is unknown. We here investigated neuroplastic changes in the cortico-cerebellar network after a five-day forearm movement training in 40 patients with mild to severe cerebellar degeneration and 40 age- and sex-matched healthy controls. Participants were assigned to one of four motor training conditions, varying online visual feedback and explicit verbal feedback. Anatomical and resting-state fMRI was collected on the days before and after training. To overcome the limitations of standard brain templates that fail in the presence of severe anatomical abnormalities, we developed a specific template for comparing cerebellar patients with age-matched controls. Our new template reduced the spatial spread of cerebellar anatomical landmarks by 30% relative to existing templates and tripled fMRI noise classification accuracy. Using this pipeline, we found that patients showed impaired connectivity between cerebellar motor regions and neocortical visuomotor and premotor regions at baseline compared to controls, whereas their cortico-cortical connectivity remained intact. Training with vision strengthened connectivity in the cortico-cerebellar visuomotor network contralateral to the trained arm in all participants. Cerebellar patients exhibited additional increased connectivity ipsilateral to the training arm in this network. Further, training with explicit verbal feedback facilitated connectivity between a cerebellar cognitive region and dorsolateral prefrontal cortex. These results indicate that motor training in cerebellar degeneration leads to enhanced functional connectivity of the cortico-cerebellar network.

neuroscience↗

bioRxiv2023

Connectome-Based Attractor Dynamics Guide Brain Activity in Rest, Task, and Disease

Functional brain connectivity has been instrumental in uncovering the large-scale organization of the brain and its relation to various behavioral and clinical phenotypes. Understanding how this functional architecture relates to the brains dynamic activity repertoire is an essential next step towards interpretable generative models of brain function. We propose functional connectivity-based Attractor Neural Networks (fcANNs), a theoretically inspired model of macro-scale brain dynamics, simulating recurrent activity flow among brain regions based on first principles of self-organization. In the fcANN framework, brain dynamics are understood in relation to attractor states; neurobiologically meaningful activity configurations that minimize the free energy of the system. We provide the first evidence that large-scale brain attractors - as reconstructed by fcANNs - exhibit an approximately orthogonal organization, which is a signature of the self-orthogonalization mechanism of the underlying theoretical framework of free-energy-minimizing attractor networks. Analyses of 7 distinct datasets demonstrate that fcANNs can accurately reconstruct and predict brain dynamics under a wide range of conditions, including resting and task states, and brain disorders. By establishing a formal link between connectivity and activity, fcANNs offer a simple and interpretable computational alternative to conventional descriptive analyses. Key PointsO_LIWe present a simple yet powerful generative computational model for large-scale brain dynamics C_LIO_LIBased on the theory of artificial attractor neural networks emerging from first principles of self-organization C_LIO_LIModel dynamics accurately reconstruct several characteristics of resting-state brain dynamics and confirm theoretical predictions of emergent attractor self-orthogonalization C_LIO_LIOur model captures both task-induced and pathological changes in brain activity C_LIO_LIfcANNs offer a simple and interpretable computational alternative to conventional descriptive analyses of brain function C_LI Project website (with interactive manuscript)https://pni-lab.github.io/connattractor

neuroscience↗

bioRxiv2021

Turning movements in real life capture subtle longitudinal and preataxic changes in cerebellar ataxia

OBJECTIVESClinical and regulatory acceptance of upcoming molecular treatments in degenerative ataxias might greatly benefit from ecologically valid endpoints which capture change in ataxia severity in patients real life. This longitudinal study aimed to unravel quantitative motor biomarkers in degenerative ataxias in real life turning movements which are sensitive for changes both longitudinally and at the preataxic stage. METHODSCombined cross-sectional (n=30) and longitudinal (n=14, 1-year interval) observational study in degenerative cerebellar disease (including 8 pre-ataxic mutation carriers) compared to 23 healthy controls. Turning movements were assessed by three body-worn inertial sensors in three conditions: (1) instructed laboratory assessment, (2) supervised free walking, and (3) unsupervised real-life movements. RESULTSMeasures which quantified dynamic balance during turning - lateral velocity change (LVC) and outward acceleration -, but not general turning measures such as speed, allowed differentiating ataxic against healthy subjects in real life with high effect size ({delta}=0.68), with LVC also differentiating preataxic against healthy subjects ({delta}=0.53). LVC was highly correlated with clinical ataxia severity (SARA score, effect size {rho}=0.79) and subjective balance confidence (ABC score, {rho}=0.66). Moreover, LVC in real life - but not general turning measures, gait measures, or the SARA score - allowed detecting significant longitudinal change in one-year follow-up with high effect size (rprb=0.66). CONCLUSIONSMeasures of turning allow to capture specific changes of dynamic balance in degenerative ataxia in real life, with high sensitivity to longitudinal differences in ataxia severity and to the preataxic stage. They thus present promising ecologically valid motor biomarkers for capturing change in real life, even in the highly treatment-relevant early stages of degenerative cerebellar disease.

bioengineering↗

bioRxiv2020

Cerebellar degeneration reduces memory resilience after extended training

Cerebellar patients are impaired in motor adaptation. Further, motor adaptation can be divided into a fast component and a slow component, and the cerebellum is known to be especially crucial for the slow component. We tested whether the cerebellar deficit in motor adaptation can be ameliorated by training paradigms targeting slow learning using four visuomotor tasks: standard, gradual, overlearning and long intertrial intervals. We measured slow learning in patients and age-matched controls using a standard paradigm developed for reaching movements by Smith in 2006. The paradigm quantifies slow learning as the magnitude of spontaneous recovery of a previously learned and washed-out adaptation. Cerebellar patients had slower learning and reached a lower level of final adaptation, as seen in previous studies. Nevertheless, both groups had robust spontaneous recovery. Moreover, spontaneous recovery was increased in both groups in the overlearning paradigm with no significant difference between them. Computational modeling suggested that increased spontaneous recovery in the Control group reflects a changed slow adaptation system. That is, in the overlearning in controls, the slow system forgot more slowly and had a slower response to errors. In contrast, the same modeling suggests that no such change in the slow system occurred in the Cerebellar group. Rather, increased spontaneous recovery in this group seems to be the result of greater accumulated slow adaptation in the overlearning. We used our modeling results to predict that overlearning should have slower adaptation in the counterperturbation. Modeling further suggested we would not see these difference in the cerebellar patients. Follow-up analysis confirmed these model predictions. Taken together, our results imply that residual slow learning in cerebellar patients is expressed during increased training trials, but the primary cerebellar deficit is not improved.

neuroscience↗

bioRxiv2019

Towards ecologically valid biomarkers: real-life gait assessment in cerebellar ataxia

BACKGROUNDWith disease-modifying drugs on the horizon for degenerative ataxias, motor biomarkers are highly warranted. While ataxic gait and its treatment-induced improvements can be captured in laboratory-based assessments, quantitative markers of ataxic gait in real life will help to determine ecologically meaningful improvements.\n\nOBJECTIVESTo unravel and validate markers of ataxic gait in real life by using wearable sensors.\n\nMETHODSWe assessed gait characteristics of 43 patients with degenerative cerebellar disease (SARA:9.4{+/-}3.9) compared to 35 controls by 3 body-worn inertial sensors in three conditions: (1) laboratory-based walking; (2) supervised free walking; (3) real-life walking during everyday living (subgroup n=21). Movement analysis focussed on measures of movement smoothness and spatio-temporal step variability.\n\nRESULTSA set of gait variability measures was identified which allowed to consistently identify ataxic gait changes in all three conditions. Lateral step deviation and a compound measure of step length categorized patients against controls in real life with a discrimination accuracy of 0.86. Both were highly correlated with clinical ataxia severity (effect size {rho}=0.76). These measures allowed detecting group differences even for patients who differed only 1 point in the SARAp&g subscore, with highest effect sizes for real-life walking (d=0.67).\n\nCONCLUSIONSWe identified measures of ataxic gait that allowed not only to capture the gait variability inherent in ataxic gait in real life, but also demonstrate high sensitivity to small differences in disease severity - with highest effect sizes in real-life walking. They thus represent promising candidates for quantitative motor markers for natural history and treatment trials in ecologically valid contexts.

bioengineering↗

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.

neuroscience↗

bioRxiv2019

Cerebellar involvement in learning to balance a cart-pole system

The role of the cerebellum in error-based motor adaptation is well examined. In contrast, the involvement of the cerebellum in reward-based motor learning is less clear. In this study, we examined cerebellar involvement in a reward-based motor learning task, namely learning to control a virtual cart-pole system, over five consecutive days. Subjects with focal cerebellar lesions were compared to age-matched controls in terms of learning performance and underlying control mechanisms.\n\nBased on the overall balancing performance we have identified two subgroups of patients: (1) patients with learning performance comparable to healthy controls and (2) patients with decelerated learning, unsaturated learning progress after five days and decreased inter-manual transfer. Furthermore, we found that online learning is impaired while offline learning is partly preserved in cerebellar subjects. Regarding control mechanisms, decreased control performance was associated with impairments in predictive action timing.\n\nVoxel-wise lesion symptom mapping based on the two subgroups revealed strong associations between impairments in controlling the virtual cart-pole system and lesions in intermediate and lateral parts of lobules V and VI. These results together with previous reports suggest that the ability to predict the dynamics of the cart-pole system is an important factor for the reward-based skill acquisition process.

neuroscience↗