Biology subjects

Fell, J.

Publications and source records attributed to Fell, J..

12 recordsLinked to original sources

bioRxiv2026

AMPK reinforces mitochondrial metabolism and suppresses pathological remodeling in Complex V-deficient cardiomyocytes

TMEM70 variants represent the most common nuclear cause of mitochondrial ATP synthase (Complex V) deficiency and are associated with particularly severe cardiac manifestations. Yet, how TMEM70 deficiency disrupts cardiomyocyte metabolic maturation and function remains poorly understood, in part because suitable human disease models are lacking. Here, we model TMEM70-related Complex V deficiency using CRISPR-engineered human induced pluripotent stem cells differentiated into cardiomyocytes. While TMEM70-deficient pluripotent cells retain mitochondrial function, differentiated cardiomyocytes develop reduced mitochondrial membrane potential, impaired respiratory capacity, and pathological remodeling, revealing a differentiation-dependent failure of metabolic maturation. Chronic activation of AMP-activated protein kinase (AMPK) restores mitochondrial respiratory capacity despite persistent Complex V deficiency. Proteomic and metabolomic analyses reveal that AMPK activation in TMEM70-deficient cardiomyocytes reinforces mitochondrial and fatty-acid metabolism while suppressing pathological structural remodeling, accompanied by improved cardiac function. Together, these findings identify AMPK-dependent metabolic remodeling as a state-dependent mechanism of functional rescue in mitochondrial cardiomyopathy.

cell biology↗

bioRxiv2025

Attention modulates hippocampal sharp-wave ripples in humans

Hippocampal sharp-wave ripples (SWRs) are high-frequency events critical for memory consolidation, typically studied during sleep and quiet wakefulness. Emerging evidence suggests that SWRs also occur during active behavior, yet their role in awake cognition remains unclear. Here, we demonstrate that changes in sustained attention modulate both the occurrence of SWRs and their temporal alignment to ongoing hippocampal oscillations. Using intracranial EEG recordings from epilepsy patients performing a sustained attention to response task (SART), we first identified attentional states based on behavioral variability and subjective reports. Next, we observed that SWRs were more frequent during high-attention periods, despite the absence of memory demands. Importantly, SWRs during low-attention periods showed higher phase synchrony with low-frequency oscillations (theta to lower beta) indicating increased endogenous coordination of SWRs under low attentional focus. These findings show that SWRs are dynamically regulated by attentional engagement, supporting a broader role for ripples in active cognitive processing.

neuroscience↗

bioRxiv2022

A key role of the hippocampal P3 in the attentional blink

The attentional blink (AB) refers to an impaired identification of target stimuli (T2), which are presented shortly after a prior target (T1) within a rapid serial visual presentation (RSVP) stream. It has been suggested that the AB is related to a failed transfer of T2 into working memory and that hippocampus (HC) and entorhinal (EC) cortex are regions crucial for this transfer. Since the event-related P3 component has been linked to inhibitory processes, we hypothesized that the hippocampal P3 elicited by T1 may impact on T2 processing within HC and EC. To test this hypothesis, we reanalyzed microwire data from 21 patients, who performed an RSVP task, during intracranial recordings for epilepsy surgery assessment (Reber et al., 2017). We identified T1-related hippocampal P3 components in the local field potentials (LFPs) and determined the temporal onset of T2 processing in HC/EC based on single-unit response onset activity. In accordance with our hypothesis, T1-related single-trial P3 amplitudes at the onset of T2 processing were clearly larger for unseen compared to seen T2-stimuli. Moreover, increased T1-related single-trial P3 peak latencies were found for T2[unseen] versus T2[seen] trials in case of lags 1 to 3, which was in line with our predictions. In conclusion, our findings support inhibition models of the AB and indicate that the hippocampal P3 elicited by T1 plays a central role in the AB.

neuroscience↗

bioRxiv2021

Ensuring scientific reproducibility in bio-macromolecular modeling via extensive, automated benchmarks

Each year vast international resources are wasted on irreproducible research. The scientific community has been slow to adopt standard software engineering practices, despite the increases in high-dimensional data, complexities of workflows, and computational environments. Here we show how scientific software applications can be created in a reproducible manner when simple design goals for reproducibility are met. We describe the implementation of a test server framework and 40 scientific benchmarks, covering numerous applications in Rosetta bio-macromolecular modeling. High performance computing cluster integration allows these benchmarks to run continuously and automatically. Detailed protocol captures are useful for developers and users of Rosetta and other macromolecular modeling tools. The framework and design concepts presented here are valuable for developers and users of any type of scientific software and for the scientific community to create reproducible methods. Specific examples highlight the utility of this framework and the comprehensive documentation illustrates the ease of adding new tests in a matter of hours.

bioinformatics↗

bioRxiv2020

Auditory beat stimulation modulates memory-related single-neuron activity in the human medial temporal lobe

Auditory beats are composed of two sine waves using nearby frequencies, which can either be applied as a superposed signal to both ears or to each ear separately. In the first case, the beat sensation results from hearing an amplitude-modulated signal (monaural beat). In the second case, it is generated by phase-sensitive neurons in the brain stem (binaural beat). We investigated the effects of monaural and binaural 5 Hz beat stimulation on neural activity and memory performance in neurosurgical patients performing an associative recognition task. Previously, we had reported that these beat stimulation conditions modulated memory performance in opposite directions. Here, we analyzed data from a patient subgroup, in which microwires were implanted in the amygdala, hippocampus, entorhinal cortex and parahippocampal cortex. We identified neurons responding with firing rate changes to binaural versus monaural 5 Hz beat stimulation. In these neurons, we correlated the differences in firing rates for binaural versus monaural beats to the memory-related differences for remembered versus forgotten items and associations. In the left hemisphere for these neurons, we detected statistically significant negative correlations between firing rate differences for binaural versus monaural beats and remembered versus forgotten items/associations. Importantly, such negative correlations were also observed between beat stimulation-related firing rate differences in the baseline window and memory-related firing rate differences in the poststimulus windows. In line with concepts of homeostatic plasticity, we interpret our findings as indicating that beat stimulation is linked to memory performance via shifting baseline firing levels.

neuroscience↗

bioRxiv2020

Saccadic modulation of neural activity in the human anterior thalamus during visual active sensing

Humans and other primates explore visual scenes by active sensing, using saccadic eye movements to relocate the fovea and sample different bits of information multiple times per second. Saccades induce a phase reset of ongoing neuronal oscillations in primary and higher-order visual cortices and medial temporal lobe. As a result, neuron ensembles are shifted to a common state at the time visual input propagates through the system (i.e., just after fixation). The extent of the brains circuitry modulated by saccades is not yet known. Here, we evaluate the possibility that saccadic phase reset impacts the anterior nuclei of the thalamus (ANT). Using rare recordings in the human thalamus of three surgical patients, we found saccade-related phase concentration, peaking at 3-4 Hz, coincident with suppression of Broadband High-frequency Activity (BHA; 80-180 Hz). Our results provide evidence for saccade-related modulation of neuronal excitability dynamics in the ANT, consistent with the idea that these nuclei are engaged during visual active sensing. These findings show that during real-world active visual exploration neural dynamics in the human ANT, a part of extended hippocampal-diencephalic system for episodic memory, exhibit modulations that might be underestimated in typical passive viewing.

neuroscience↗

bioRxiv2020

Sharp-wave ripples in human amygdala and their coordination with hippocampus

Cooperative interactions between the amygdala and hippocampus are widely regarded as critical for overnight emotional processing of waking experiences, but direct support from the human brain for such a dialog is absent. Using intracranial recordings in four pre-surgical epilepsy patients (two male, two female), we discovered ripples within human amygdala during non-rapid eye movement (NREM) sleep. Like hippocampal ripples, amygdala ripples are strongly associated with sharp waves, are linked to sleep spindles, and tend to co-occur with their hippocampal counterparts. Moreover, sharp waves and ripples are temporally linked across the two brain structures, with amygdala ripples occurring during hippocampal sharp waves and vice versa. Combined with further evidence of interregional sharp wave and spindle synchronization, these findings offer a potential physiological substrate for the NREM-sleep-dependent consolidation and regulation of emotional experiences.

neuroscience↗

bioRxiv2019

Phase-based coordination of hippocampal and neocortical oscillations during human sleep

During sleep, new memories undergo a gradual transfer from the hippocampus (HPC) to the neocortex (NC). Precisely timed neural oscillations interacting within and between these brain structures are thought to mediate this sleep-dependent memory consolidation, but exactly which sleep oscillations instantiate the HPC-NC dialog, and via what mechanisms, remains elusive. Employing invasive electroencephalography in ten neurosurgical patients across a full night of sleep, we identified three broad classes of phase-based HPC-NC communication. First, we observed interregional phase synchrony for non-rapid eye movement (NREM) spindles, N2 and rapid eye movement (REM) theta, and N3 beta activity. Second, and most intriguingly, we found asymmetrical N3 cross-frequency phase-amplitude coupling between HPC SOs and NC activity spanning the delta to high-gamma/ripple bands, but not in the opposite direction. Lastly, N2 theta and NREM spindle synchrony were themselves modulated by HPC SOs. These novel forms of phase-based interregional communication emphasize the role of HPC SOs in the HPC-NC dialog, and may offer a physiological basis for the sleep-dependent reorganization of mnemonic content.

neuroscience↗

bioRxiv2019

Sleep spindles mediate hippocampal-neocortical coupling during sharp-wave ripples

Sleep is pivotal for the consolidation of memories [1]. According to two-stage accounts, experiences are temporarily stored in the hippocampus and gradually translocated to neocortical sites during non-rapid-eye-movement (NREM) sleep [2,3]. Mechanistically, information transfer is thought to rely on interactions between thalamocortical spindles and hippocampal ripples. In particular, spindles may open precisely-timed communication channels, across which reactivation patterns may travel between the hippocampus and cortical target sites when ripples occur. To test this hypothesis, we first derived time-frequency representations (TFRs) in hippocampus (HIPP) and at scalp electrode Cz (neocortex, NC) time-locked to individual hippocampal ripple events. Compared to matched ripple-free intervals, results revealed a concurrent increase in spindle power both in HIPP and NC. As revealed by coherence analysis, hippocampal-neocortical coupling was indeed enhanced in the spindle band around ripples. Finally, we examined the directionality of spindle coupling and observed a strong driving effect from NC to HIPP. Specifically, [~]250 ms prior to the HIPP ripple, NC spindles emerge and entrain HIPP spindles. Both regions then remain synchronised until [~]500 ms after the ripple. Consistent with recent rodent work, these findings suggest that active consolidation is initiated by neocortex and draws on neocortical-hippocampal-neocortical reactivation loops [4], with a role of sleep spindles in mediating this process.

neuroscience↗

bioRxiv2019

Heterogeneous profiles of coupled sleep oscillations in human hippocampus

Cross-frequency coupling of sleep oscillations is thought to mediate memory consolidation. While the hippocampus is deemed central to this process, detailed knowledge of which oscillatory rhythms interact in the sleeping human hippocampus is lacking. Combining intracranial hippocampal and non-invasive electroencephalography from twelve neurosurgical patients, we characterized spectral power and coupling during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Hippocampal coupling was extensive, with the majority of channels expressing spectral interactions. NREM consistently showed delta-ripple coupling, but ripples were also modulated by slow oscillations (SOs) and sleep spindles. SO-delta and SO-theta coupling, as well as interactions between delta/theta and spindle/beta frequencies also occurred. During REM, limited interactions between delta/theta and beta frequencies emerged. Moreover, oscillatory organization differed substantially between i) hippocampus and scalp, ii) sites along the anterior-posterior hippocampal axis, and iii) individuals. Overall, these results extend and refine our understanding of hippocampal sleep oscillations.

neuroscience↗

bioRxiv2017

Alpha activity in the ventral and dorsal visual stream controls information flow during working memory

The electrophysiological mechanisms underlying working memory maintenance of information in the ventral and dorsal visual stream (VVS, DVS) remain elusive. Here we used electrocorticography recordings covering VVS, DVS and prefrontal cortex (PFC) in epilepsy patients while they were performing a delayed match-to-sample task. The experimental conditions (face identity, orientation) were designed to engage either the VVS or DVS. Alpha power was reduced in the VVS during maintenance of face identity and in the DVS during maintenance of spatial orientation of the very same stimuli. The phase of alpha oscillations modulated broadband high-frequency activity (BHA) in both regions. Interestingly, BHA occurred across broader alpha phase ranges when task-relevant information was maintained, putatively reflecting longer excitable \"duty cycles\". Our findings support a model in which the VVS and DVS are recruited by the PFC via selective reduction of alpha power. As a result, excitable duty cycles in the relevant area are extended.

neuroscience↗

bioRxiv2017

Theta Phase Synchronization Between The Human Hippocampus And The Prefrontal Cortex Supports Learning Of Unexpected Information

Events that violate predictions are thought to not only modulate activity within the hippocampus and prefrontal cortex, but also to enhance communication between the two regions. Several studies in rodents have shown that synchronized theta oscillations facilitate communication between the prefrontal cortex and hippocampus during salient events, but it remains unclear whether similar oscillatory mechanisms support interactions between the two regions in humans. Here, we had the rare opportunity to conduct simultaneous electrophysiological recordings from the human hippocampus and prefrontal cortex from two patients undergoing presurgical evaluation for pharmaco-resistant epilepsy. Recordings were conducted during a task that involved encoding of contextually expected and unexpected visual stimuli. Across both patients, hippocampal-prefrontal theta phase synchronization was significantly higher during encoding of unexpected study items, compared to contextually expected study items. In contrast, we did not find increased theta synchronization between the prefrontal cortex and rhinal cortex. Our findings are consistent with the idea that theta oscillations orchestrate communication between the hippocampus and prefrontal cortex during the processing of contextually salient information.

neuroscience↗