Biology subjects

Axmacher, N.

Publications and source records attributed to Axmacher, N..

At least 19 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.

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bioRxiv2026

How Awakenings Shape Dream Recall: A Multilevel Study

Dream recall varies substantially both between individuals and from night to night within the same individual. Although nocturnal awakenings are thought to facilitate the encoding and later retrieval of dream experiences, it remains unclear whether dream recall is shaped primarily by awakening frequency or by more specific awakening characteristics, including duration, sleep stage, and timing within the night. Here, we analyzed two cohorts: cohort 1 consisted of 708 adults spanning the full range of dream recall frequency, assessed across three waves with home sleep recordings and questionnaire-based dream recall frequency measures; cohort 2 consisted of 124 adults with high dream recall frequency, assessed across multiple nights with home sleep recordings and daily dream reports. Using multilevel models with within-between decomposition, we examined trait-like and state-like associations between awakening measures and dream recall outcomes. At the trait level, both questionnaire-based dream recall frequency in cohort 1 and daily dream recall (i.e., a sense of having dreamed) in cohort 2 were associated with a specific nocturnal awakening profile: more habitual long REM awakenings and short NREM awakenings, with REM awakening effects remaining robust after adjustment for sleep duration. At the state level, in cohort 2, nights with more short and medium REM awakenings than usual increased the likelihood of morning dream recall, whereas nights with more long REM awakenings than usual increased the likelihood of morning dream content recall (i.e., remembering dream content). These findings support the arousal-retrieval and functional state-shift models, while highlighting important nuances in the associations between nocturnal awakenings and different dream recall outcomes.

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bioRxiv2026

Multiscale Mechanisms of Human Memory Modulation by Deep Brain Stimulation

The highly variable effects of deep brain stimulation (DBS) on cognition highlight a fundamental gap in our understanding of how external perturbations interface with the brains ongoing, task-engaged state. The current study addressed this challenge by combining intracranial EEG recordings with hippocampal DBS stimulation in human participants during spatial sequence memory task. We found 50 Hz stimulation targeting hippocampal white matter enhanced memory performance, whereas 5 Hz stimulation targeting hippocampal gray matter impaired memory. These opposing behavioral outcomes were both governed by two dissociated mechanisms: a region-specific modulation of theta rhythms in an engagement-dependent fashion, and a global modulation of the fidelity of memory representations across the cortex. Our results suggest targeted stimulation can concurrently fine-tune specialized circuits and govern the brains global state, which not only offers a novel roadmap for understanding how external inputs shape human cognition, but also helps to design precise, state-dependent neuromodulation therapies.

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bioRxiv2026

Ramping-up hippocampal ripples and their neocortical coupling support human visual short-term memory

Emerging evidence suggests that the hippocampus contributes to visual short-term memory (VSTM). However, the neural mechanisms through which hippocampal activity supports the maintenance of VSTM representations remain largely unknown. Here, using intracranial EEG recordings from human participants performing a delayed match-to-sample task for naturalistic objects, we investigated the role of hippocampal ripple activity--brief high-frequency oscillations associated with memory replay--in VSTM maintenance and hippocampal-neocortical communication. We found that hippocampal ripple rates progressively ramped up during the maintenance period and supported successful VSTM. More critically, hippocampal ripples were temporally coupled with the ripples in the lateral temporal lobe (LTL), and these coupled ripples were associated with memory reactivation in the LTL. These findings provide direct evidence that hippocampal-neocortical interaction via coupled ripples supports VSTM, extending the role of hippocampal ripples from long-term consolidation to short-term mnemonic processes and offering new insights into the dynamic coding mechanisms of working memory. Impact StatementHippocampal ripple ramping-up and neocortical coupling support a dynamic coding mechanism for visual short-term memory maintenance

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bioRxiv2025

It's All In The Journey: Putative Strategies Extracted from Navigation Paths Predict Spatial Memory and Hippocampal Recruitment

Navigation in the real world may rely on a multitude of different strategies with distinct advantages and disadvantages. However, the characterization of spontaneous strategy use during wayfinding and underlying neural correlates are scarce. We explore data across three groups of participants who performed a virtual navigation task: (I) epilepsy patients undergoing invasive electrophysiological recordings of the hippocampus, and two groups who underwent fMRI scanning: (II) young adults at genetic risk for Alzheimers disease (APOE-e4 carriers) and (III) healthy controls. We establish three metrics by which to quantitatively characterize each taken path, with the aim of simultaneously reflecting the putative strategies used by humans to solve the task: 1. straightness of paths; 2. deviation towards the edge of the circular arena; and 3. overlap of individual paths leading to a specific object location, which putatively relate to reliance on allocentric (1) and egocentric reference frames (2 & 3). Extracted metrics were related to performance in the task and to hippocampal activity. We find that strategy use is variable within participant, changes across the experiment, and is adaptive in a group-dependent manner. While hippocampal BOLD activity and theta (gamma) power were generally inversely (positively) related, we found that the recruitment of the hippocampus was both group- and strategy- specific. Our results further our understanding of the heterogeneous and idiosyncratic nature of spatial navigation by revealing, how these behaviors are altered by disease and the subsequent compensatory neural dynamics, as well as the link between mesoscopic and macroscopic neural signals.

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bioRxiv2025

Blood volume sensitive laminar fMRI with VASO in human hippocampus: Capabilities and biophysical challenges at clinical 7T scanners

Sub-millimeter resolution functional magnetic resonance imaging (fMRI) at ultra-high field ([≥] 7T) has offered an unprecedented opportunity to probe mesoscopic computations at a columnar or laminar level. However, its application has been primarily restricted to the neocortex. Inferior brain regions, particularly the hippocampus (HC), are challenging targets for laminar fMRI. Recent developments in acquisition methods have shown the feasibility of laminar recordings in the HC using gradient-echo blood oxygenation level-dependent (BOLD) contrast. Nonetheless, the spatial specificity of the BOLD signal is compromised by the draining veins bias. Cerebral blood volume (CBV)-sensitive sequences including vascular space occupancy (VASO) have emerged as a promising augmentation tool to capture the vein-free laminar activity. Yet, its feasibility in the HC is unclear and challenged by methodological constraints. Here, we optimized VASO to mitigate the macrovasculature contribution in HC. By evaluating a series of advanced acquisition strategies tailored to HC, we obtained improved VASO signal quality with minimal artifacts. The optimized protocol was further validated with an autobiographical memory task. Our findings show that combining the high detection power of gradient-echo BOLD with the vein-free VASO contrast allows for differentiation between neural activity-related BOLD signals and those biased by draining veins. These results demonstrate the feasibility of submillimeter VASO acquired with conventional 7T scanners in the HC to map the circuit-level mechanisms of memory retrieval across HC subfields, laying a foundation to investigate the microcircuitry of HC-driven complex cognitive functions and their alterations in neurodegeneration.

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bioRxiv2025

Task-relevant cognitive maps in episodic memory

Adaptive behavior requires stimuli to be processed in a way that meets the requirements of the current task. This is especially relevant for natural concepts that comprise a multitude of representational formats. The medial temporal lobe (MTL) has been proposed to support such flexibility by organizing stimuli within relational representational spaces serving as cognitive maps. However, while various studies investigated the formation of novel cognitive maps based on abstract features, it remains unclear how our vast existing conceptual knowledge is recruited into task-relevant representational spaces and whether these spaces influence the formation of novel episodic memories. Here we show that neural representations of natural concepts in the MTL and neocortex are embedded in low-dimensional representational spaces of task-relevant features that flexibly reorganize when task demands change. Crucially, hippocampal pattern similarity reflects task-relevant, but not task-irrelevant conceptual feature dimensions of the same set of natural concepts, indicating context-dependent reconfiguration of representational spaces. Euclidean distances within and across these spaces predicted subsequent memory confidence for individual items, suggesting a putative metric of task-dependent neural distinctiveness for the formation of memory traces. Finally, we dissociate task- and stimulus-dependent formats in neocortex, demonstrating complementary representations of natural stimuli that differentially contribute to memory formation. Our findings suggest that relational coding of task-relevant features in the MTL may serve as an index of representational distinctiveness that contributes to the formation of novel episodic memories and integrate MTL accounts based on spatial coding and episodic memory.

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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

Representational dynamics during extinction of fear memories in the human brain

Extinction learning - the suppression of a previously acquired fear response - is critical for adaptive behavior and core for understanding the etiology and treatment of anxiety disorders. Electrophysiological studies in rodents have revealed critical roles of theta (4-12Hz) oscillations in amygdala and hippocampus during both fear learning and extinction, and engram research has shown that extinction relies on the formation of novel, highly context-dependent memory traces that suppress the initial fear memories. Whether similar processes occur in humans and how they relate to previously described neural mechanisms of episodic memory formation and retrieval remains unknown. Intracranial EEG (iEEG) recordings in epilepsy patients provide direct access to the deep brain structures of the fear and extinction network, while representational similarity analysis (RSA) allows characterizing the memory traces of specific cues and contexts. Here we combined these methods to show that amygdala theta oscillations during extinction learning signal safety rather than threat and that extinction memory traces are characterized by stable and context-specific neural representations that are coordinated across the extinction network. We further demonstrate that context specificity during extinction learning predicts the reoccurrence of fear memory traces during a subsequent test period, while reoccurrence of extinction memory traces predicts safety responses. Our results reveal the neurophysiological mechanisms and representational characteristics of context-dependent extinction learning in the human brain. In addition, they show that the mutual competition of fear and extinction memory traces provides a mechanistic basis for clinically important phenomena such as fear renewal and extinction retrieval.

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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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bioRxiv2024

Distinct representational properties of cues and contexts shape fear learning and extinction

When we learn that something is dangerous, a fear memory is formed. However, this memory is not fixed and can be updated through new experiences, such as learning that the threat is no longer present. This process of updating, known as extinction or reversal learning, is highly dependent on the context in which it occurs. How the brain represents cues, contexts, and their changing threat value remains a major question. Here, we used functional magnetic resonance imaging and a novel fear learning paradigm to track the neural representations of stimuli across fear acquisition, reversal, and test phases. We found that initial fear learning creates generalized neural representations for all threatening cues in the brains fear network. During reversal learning, when threat contingencies switched for some of the cues, two distinct representational strategies were observed. On the one hand, we still identified generalized patterns for currently threatening cues, whereas on the other hand, we observed highly stable representations of individual cues (i.e., item-specific) that changed their valence, particularly in the precuneus and prefrontal cortex. Furthermore, we observed that the brain represents contexts more distinctly during reversal learning. Furthermore, additional exploratory analyses showed that the degree of this context specificity in the prefrontal cortex predicted the subsequent return of fear, providing a potential neural mechanism for fear renewal. Our findings reveal that the brain uses a flexible combination of generalized and specific representations to adapt to a changing world, shedding new light on the mechanisms that support cognitive flexibility and the treatment of anxiety disorders via exposure therapy.

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bioRxiv2024

Task-relevant representational formats in multi-layered memory traces

During encoding, stimuli are embedded into memory traces that allow for their later retrieval. However, we cannot remember every aspect of our experiences. Here, we show that memory traces consist of multidimensional representational spaces whose formats are flexibly strengthened or weakened during encoding and consolidation. In a series of behavioral experiments, participants compared pairs of natural images on either two conceptual or two perceptual dimensions, leading them to incorporate the images into representational "spaces". We found that distances in task-relevant but not irrelevant spaces affected memory strengths. Interestingly, conceptual encoding did not impair subsequent rejection of similar lures, suggesting that task-irrelevant perceptual information remained in the memory trace. However, targeted memory reactivation following conceptual encoding deteriorated perceptual discrimination, indicating that it weakened the accessibility of perceptual formats. Our results demonstrate that representational formats are flexibly incorporated into memory, and more generally show how the organization of information in cognitive representational spaces shapes behavior.

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bioRxiv2024

Characterizing BOLD activation patterns in the human hippocampus with laminar fMRI

The human hippocampus has been extensively studied at the macroscale using functional magnetic resonance imaging (fMRI) but the underlying microcircuits at the mesoscale (i.e., at the level of layers) are largely uninvestigated in humans. We target two questions fundamental to hippocampal laminar fMRI: How does the venous bias affect the interpretation of hippocampal laminar responses? And can we establish a benchmark laminar fMRI experiment which robustly elicits single-subject hippocampal activation utilizing the most widely applied GRE-BOLD contrast? We comprehensively characterized GRE-BOLD responses as well as T2*, tSNR and physiological noise as a function of cortical depth in individual subfields of the human hippocampus. Our results show that the vascular architecture differs between subfields leading to subfield-specific laminar biases of GRE-BOLD responses. Using an autobiographical memory paradigm, we robustly acquired depth-specific BOLD responses in hippocampal subfields. In the CA1 subregion, our results indicate a more pronounced trisynaptic path input rather than dominant direct inputs from entorhinal cortex during autobiographical memory retrival. Our study provides unique insights into the hippocampus at the mesoscale level, and will help interpreting hippocampal laminar fMRI responses and allow researchers to test mechanistic hypotheses of hippocampal function.

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bioRxiv2023

Neocortico-hippocampal ripple-based coordination during naturalistic encoding

Ripples are fast oscillatory events widely recognized as crucial markers for memory consolidation and neural plasticity. These transient bursts of activity are thought to coordinate information transfer between the hippocampus and neocortical areas, providing a temporal framework that supports the stabilization and integration of new memories. However, their role in human memory encoding during naturalistic scenarios remains unexplored. Here, we recorded intracranial electrophysiological data from ten epilepsy patients watching a movie. Ripples were analyzed in the hippocampus and in neocortical regions (i.e., temporal and frontal cortex). Our results revealed a differential dynamical pattern of ripple occurrence during encoding. Enhanced hippocampal ripple recruitment was observed at event boundaries, reflecting hippocampal involvement in event segmentation, whereas higher ripple rates were seen within an event for cortical electrodes with higher ripple occurrence at the temporal cortex reflecting weather an event was later recalled. These findings shed light on the neural mechanisms underlying memory encoding and provide insights into the potential role of ripples in the encoding of an event, suggesting an impact in the formation of long-term memories of distinct episodes.

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bioRxiv2023

Phase-Precession-Like Effects in the Anterior Insula Cortex during Reward Expectancy

Reward expectancy shapes behavioral performance by coordinating the allocation of cognitive resources, which incorporates the involvement of the anterior insular cortex (AIC). To investigate the electrophysiological mechanisms of the AIC during reward expectancy, we collected intracranial electroencephalographic data from epilepsy patients undergoing clinical monitoring. Subjects navigated a virtual T-maze containing rewards at three predetermined locations. We focused on the period immediately before entering the reward zone, termed the reward expectancy stage. During this stage, we identified the reward-specific brain patterns (RBPs) that were preactivated in the AIC. This pre-activation preceded the emergence of robust phase-amplitude coupling (PAC), where theta oscillations (5-7 Hz) modulated gamma activities (75-110 Hz). The PAC strength correlated positively with the pre-activation level of RBPs, implying the potential role of oscillatory coordination in amplifying preactivated reward representations. Strikingly, this PAC effect exhibited a specific temporal structure that peak gamma activity became progressively coupled to earlier theta phases as reward approached, mirroring the theta phase precession phenomenon previously observed in frontal and temporal lobes. We refer to this dynamic as phase-precession-like effect (PPLE). Moreover, subjects exhibiting PPLE in the AIC presented greater trial-by-trial improvements in response latency. Taken together, these findings shed light on the electrophysiological mechanisms of the AIC underlying reward expectancy.

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bioRxiv2023

Modeling the impact of genotype, age, sex, and continuous navigation on pathway integration performance

The Path Integration (PI) task stands as a fundamental activity within spatial navigation, encompassing a multifaceted underlying process that requires extensive computation of both translational and directional information during navigation. This task is postulated to engage the entorhinal cortex (EC), a critical brain region. Although rodent studies have firmly linked the EC with the PI task, such a correlation has yet to be definitively established in humans. Individuals harboring high-risk genes associated with Alzheimers disease (AD) present a unique opportunity to explore PI task performance in humans because EC is the first targeted region during the pathological development of AD. Furthermore, the execution of the PI task is also susceptible to the influences of age and gender. In order to methodically probe the influences of various factors on PI performance, we conducted a PI task in a cohort characterized by high-risk AD-associated genes in a virtual island environment with surrounding landmarks. Our findings unveiled intricate interactions between these risk genes, age, and gender in shaping PI performance, an influence primarily mediated through distance and angle estimation. This study provides an illuminating perspective on the investigation into the functional role of the entorhinal cortex within the context of the PI task.

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bioRxiv2023

Maintenance of colour memoranda in activity-quiescent working memory states: Evidence from impulse perturbation

The neural mechanisms underlying working memory maintenance pose a challenge for investigation, as sustained neural activity may not always be observable. To address this, the method of impulse perturbation has been employed to examine memorized information during activity-quiescent periods. However, this approach has mainly focused on spatially localized or referenced stimuli, leaving it unclear whether non-spatial memoranda share similar neural maintenance mechanisms. This study aimed to fill this gap by applying the impulse perturbation method to working memory for colours, which are inherently non-spatial stimuli. EEG data from 30 participants performing a delayed match-to-sample task were analysed, with one of the presented items being retro-cued as task-relevant. Our findings indicate that both cued and uncued colours could be decoded from impulse-evoked activity, in contrast to previous reports on working memory for orientation gratings. Additionally, we explored colour decoding from ongoing oscillations in the alpha band and discovered that cued items could be decoded, potentially influenced by attention, whereas uncued items could not. These results suggest subtle differences between the representation of colours and stimuli with spatial properties. However, they also demonstrate that both types of information can be accessed through visual impulse perturbation, regardless of their specific neural states.

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