Biology subjects

Nitsche, M.

Publications and source records attributed to Nitsche, M..

10 recordsLinked to original sources

bioRxiv2026

Determining Reliable Neural Targets for enhancing Motor Sequence Learning: A preparatory study for focal tDCS

BackgroundMotor sequence learning (MSL) underlies the acquisition of everyday skilled movements, and transcranial direct current stimulation (tDCS) has shown promise for enhancing it, although reported effects vary considerably. Before such interventions can be applied and interpreted reliably, the behavioural and neural signatures of the underlying task should be shown to be robust. This study therefore characterised an fMRI-based Serial Reaction Time Task (SRTT) protocol and evaluated the consistency of its behavioural and fMRI-based neural signatures in repeated measurements to identify potential network targets for tDCS. MethodsTwenty healthy young- to middle-aged adults (10 females; mean age 24, SD 4) performed the SRTT during 3T fMRI in two sessions about one week apart, each using one of two matched, non-overlapping task versions in counterbalanced order. We examined block-wise behaviour, task-related and sequence-specific brain activation (general task activation relative to baseline and the SEQ > RND contrast), and functional connectivity using two complementary approaches: the task and temporal dynamics of seed-based connectivity (SBC) within an a priori-defined motor network (M1, SMA, PMC, putamen, and cerebellum), and whole-brain generalised psychophysiological interaction (gPPI) for the SEQ > RND contrast. ResultsReaction time decreased steadily across sequence blocks and returned toward baseline during random blocks, confirming implicit sequence learning; this pattern was consistent across both sessions and both task versions. Test-retest reliability was excellent for random-block reaction time (ICC {approx} .80 - .85), and modest for sequence blocks (ICC {approx} .29 - .53). General task activation (sequence and random performance relative to baseline) engaged the expected sensorimotor network, including the primary motor cortex (M1), premotor cortex, and SMA, with M1 more strongly engaged during sequence than random blocks. The sequence-specific contrast (SEQ > RND) additionally revealed six clusters spanning the left superior parietal cortex, bilateral supplementary and cingulate motor areas, bilateral secondary somatosensory cortex, and left ventral visual cortex together with cerebellar Crus I. The a priori defined motor network was engaged across all task phases and was anchored throughout by strong M1-SMA coupling, with overall network coupling following a non-monotonic course across the session, consistent with successive stages of resource allocation, consolidation, and automatisation. The gPPI analysis identified four sequence-specific connectivity clusters, dominated by a right-lateralised visuomotor network and a somatosensory-visual integration channel. ConclusionsTogether, these findings indicate a two-component architecture for SRTT performance: a left hemispheric cortico-striato-cerebellar network that supports performance and acquisition of the sequence, and a right hemispheric network associated with monitoring its predictable structure. Within this protocol, the SRTT produced robust and stable group-level signatures of implicit motor learning, yielding well-defined network targets for future tDCS interventions..

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

Plasticity induction in the ventromedial prefrontal cortex during REM sleep improves fear extinction memory consolidation

Anxiety disorders (ADs) are among the most prevalent mental health conditions, yet first-line treatments often yield only moderate effectiveness. The fear conditioning paradigm is commonly used to investigate fear and extinction learning, revealing deficits in these processes and dysfunctional activity in the ventromedial prefrontal cortex (vmPFC) and amygdala in individuals with ADs. The vmPFC plays a critical role in regulating activity of the amygdala and consolidation of fear extinction memory. Notably, transcranial direct current stimulation (tDCS) has shown promise in enhancing fear extinction by modulating vmPFC activity. Additionally, rapid eye movement (REM) sleep has been suggested to be crucial for fear extinction memory consolidation. This study investigated the role the vmPFC during REM sleep in fear extinction memory consolidation. Thirty-two participants underwent a 3-day differential fear conditioning paradigm, with tDCS or sham stimulation applied during REM sleep over the vmPFC. Outcome measures included skin conductance responses (SCR) and subjective ratings of arousal, fear, and valence. Results indicate that tDCS during REM sleep enhances fear extinction memory consolidation, as measured by SCR. Furthermore, participants reported an increased subjective arousal following tDCS. These findings suggest that tDCS during REM sleep may hold potential for improving exposure-based treatments for ADs by strengthening fear extinction memory.

neuroscience↗

bioRxiv2025

Phase-synchronized 40 Hz transcranial electric and magnetic stimulation boosts gamma oscillations and working memory

Gamma oscillations play a crucial role in core cognitive functions such as memory processes. Enhancing gamma oscillatory activity, which is reduced in Alzheimers Disease, may have therapeutic potential, but effective interventions remain to be determined. Previous studies have shown that phase-synchronized electric and magnetic stimulation boosts brain oscillatory activities at theta, alpha, and delta frequency bands in different ways. The high-frequency gamma frequency band remains to be investigated. This study applies novel noninvasive brain stimulation techniques, namely phase-locked 40-Hz intermittent theta-burst stimulation (iTBS) and transcranial alternating current stimulation (tACS), and explores gamma oscillation changes in the brain. Thirty healthy young participants randomly underwent 40-Hz tACS (1), 40-Hz iTBS (2), two combined interventions (phase-locked iTBS to tACS peak sine wave or tACS trough sine wave) (3-4), and a sham condition (5). The target regions were the left and right dorsolateral prefrontal cortex and were stimulated by simultaneous tACS and iTBS. Gamma oscillatory activities (for 2 hours after intervention) were monitored following each intervention. Our results show that all stimulation protocols enhanced 40-Hz oscillatory power. The iTBS-tACS Peak shows the most significant and stable increase in gamma oscillatory activities (up to 2 hours), followed by 40-Hz tACS and 40-Hz iTBS. 40-Hz tACS and 40-Hz iTBS had the strongest acute effects (up to 30 min) on induced gamma oscillations, while 40-Hz tACS most consistently induced gamma oscillations for up to 2 hours in overall resting EEG data. Phase-synchronizing iTBS with tACS at 40 Hz and the 40 Hz tACS alone targeting the dorsolateral prefrontal cortex, may be a viable approach for inducing and stabilizing gamma oscillatory activity, particularly in conditions where endogenous gamma oscillatory is attenuated, such as Alzheimers Disease. Registration IDs:101017716 (CORDIS - European Union-funded project)

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

Multimodal assessment of acute stress dynamics using an Aversive Video Paradigm (AVP)

This study explored the efficacy of inducing stress through aversive video clips and investigated its impact on psychological processes, brain, and vegetative physiology. It had a randomized, single-blinded, crossover design, where participants were exposed in separate sessions to aversive or neutral video clips. Subjective feelings of stress were assessed via questionnaires. Electroencephalography (EEG) with 62 electrodes was recorded continuously. EEG power and connectivity changes based on coherence were analyzed. Heart rate (HR) and heart rate variability (HRV) data were obtained during the whole experiment, and saliva was collected for cortisol and cytokine analysis at different time intervals. Subjective data showed increased anxiety and negative affect induced by the aversive video clips, accompanied by elevated salivary cortisol levels after exposure to the stressful clips, and decreased heart rate variability. Cytokine levels however increased over time in both control and stress conditions, which argues against a stress-specific alteration of cytokines in this specific stress protocol. EEG alterations during stress induction suggest a disruption of top-down control and increased bottom-up processing. These results show that aversive video clips are suited to induce psychological stress in an experimental setting reliably, and are associated with stress-specific emotional, and physiological changes.

neuroscience↗

bioRxiv2022

Transferability of cathodal tDCS effects from the primary motor to the dorsolateral prefrontal cortex: a multimodal TMS-EEG study

Neurophysiological effects of transcranial direct current stimulation (tDCS) have been extensively studied over the primary motor cortex (M1). Much less is however known about its effects over non-motor areas, such as the prefrontal cortex (PFC), which is the neuronal foundation for many high-level cognitive functions and involved in neuropsychiatric disorders. In this study, we, therefore, explored the transferability of cathodal tDCS effects over M1 to the PFC. Eighteen healthy human participants (11 males and 8 females) were involved in eight randomized sessions, in which four cathodal tDCS dosages, low, medium, and high, as well as sham stimulation, were applied over the M1 and PFC. After-effects of tDCS were evaluated via transcranial magnetic stimulation (TMS)-electroencephalography (EEG), and TMS-elicited motor evoked potentials (MEP), for the outcome parameters TMS-evoked potentials (TEP), TMS-evoked oscillations, and MEP amplitude alterations. TEPs were studied both at the regional and global scalp levels. The results indicate a regional dosage-dependent nonlinear neurophysiological effect of M1 tDCS, which is not one-to-one transferable to PFC tDCS. Low and high dosages of M1 tDCS reduced early positive TEP peaks (P30, P60), and MEP amplitudes, while an enhancement was observed for medium dosage M1 tDCS (P30 and MEP amplitudes). In contrast, prefrontal low, medium and high dosage tDCS uniformly reduced the early positive TEP peak amplitudes. Furthermore, for both cortical areas, regional tDCS-induced modulatory effects were not observed for late TEP peaks, nor TMS-evoked oscillations. However, at the global scalp level, widespread effects of tDCS were observed for both, TMS-evoked potentials and oscillations. This study provides the first direct physiological comparison of tDCS effects applied over different brain areas and therefore delivers crucial information for future tDCS applications. SIGNIFICANCE STATEMENTModulatory effects of tDCS over the M1 were largely taken as a template so far for the use of this intervention over non-motor regions. However, the neurophysiological effects of tDCS over non-motor regions, such as the prefrontal cortex (PFC), have been much less explored. In the current study, we, using concurrent transcranial magnetic stimulation- electroencephalography, systematically explored the transferability of cathodal tDCS effects on cortical excitability from M1 to the PFC. The results indicate a dosage-dependent nonlinear neurophysiological effect of motor cortex tDCS, which is not one-to-one transferable to prefrontal tDCS. This study provides the first direct physiological comparison of tDCS effects applied over different brain areas, which will further consolidate the rationale for the extension of tDCS applications at both, basic and clinical levels.

neuroscience↗

bioRxiv2021

Sleep-dependent upscaled excitability and saturated neuroplasticity in the human brain: From brain physiology to cognition

Sleep strongly affects synaptic strength, making it critical for cognition, especially learning, and memory formation. Whether and how sleep deprivation modulates human brain physiology and cognition is not well understood. Here we examined how overnight sleep deprivation vs sufficient sleep affects (a) cortical excitability, as measured by transcranial magnetic stimulation (TMS), (b) inducibility of LTP-and-LTD-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory and attention. The results suggest that sleep deprivation upscales cortical excitability due to enhanced glutamate-related cortical facilitation and decreased and/or reversed GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity abolishes while LTD-like plasticity converts to excitatory LTP-like plasticity under sleep deprivation. This is associated with increased EEG theta activity, which is related to sleep pressure. Finally, we show that learning and memory formation, behavioral counterparts of plasticity, and working memory and attention, which rely on cortical excitability, are impaired during sleep deprivation. Our data suggest that upscaled brain excitability, and altered plasticity, due to sleep deprivation, are associated with impaired cognitive performance.

neuroscience↗

bioRxiv2020

Capitalizing on paradoxical activation of the MAPK pathway for treatment of Imatinib-resistant mast cell leukemia and chronic myelogenous leukemia

Prevention of fatal side effects during cancer therapy of cancer patients with high-dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug-mediated dimerization of RAF kinases can be the cause of acquired resistance, also called "paradoxical activation". Here we re-analyzing the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib-resistant, KITV560G,D816V-expressing human mast cell (MC) leukemia (MCL) cell line HMC-1.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF-CRAF dimerization, resulting in ERK1/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC-1.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSA KITD816V and in KIT D816V hematopoietic progenitors obtained from in patient-derived induced pluripotent stem cells (iPS cells). In conclusion, mutated KIT-driven Imatinib resistance can be efficiently bypassed by a low concentration combination of the TKI Ponatinib and the MEK inhibitor Trametinib, potentially reducing the negative side effects associated to MCL therapy.

cancer biology↗

bioRxiv2020

Multifocal tDCS modulates resting-state functional connectivity in older adults depending on induced electric field and baseline connectivity

BackgroundAdvancing age affects the brains resting-state functional networks. Combining non-invasive brain stimulation (NIBS) with neuroimaging is a promising approach to modulate activity across resting-state functional systems and explore their true contribution to cognitive function in aging. However, substantial individual variability in the response to NIBS has been reported and, hence, identifying the individual predictors of NIBS-induced modulatory effects is crucial if we are to harness their potential. MethodsThirty-one cognitively healthy older adults (71.68 {+/-} 2.5 years; 19 females) underwent two different multifocal real tDCS conditions (C1 and C2) and a sham condition in a crossover design during a resting-state functional magnetic resonance imaging (rs-fMRI) acquisition. The real tDCS conditions were designed to induce two distinct electric field distribution patterns either targeting generalized cortical overactivity or a dissociation between the frontal areas and the posteromedial cortex. Stimulation was delivered through an MRI-compatible device using 8 small circular electrodes. Each individuals anatomical T1-weighted MRI was used to generate a finite element model to define the individual electric field generated by each tDCS condition. ResultsThe two tDCS conditions modulated resting-state connectivity differently. C1 increased the coactivation of numerous functional couplings as compared to sham, however, a smaller amount of connections increased in C1 as compared to C2, while no differences between C2 and sham were appreciated. At the group level, C1-induced modulations primarily included temporo-occipital areas and distinct cerebellar regions. This functional pattern was anatomically consistent with the estimated distribution of the induced electric field in the C1 condition. Finally, at the individual level, the extent of tDCS-induced rs-fMRI modulation in C1 was predicted by baseline resting-state connectivity and simulation-based electric field magnitude. DiscussionOur results highlighted that multifocal tDCS procedures can effectively change neural dynamics in the elderly consistently with the spatial distribution of the estimated electric fields on the brain. Furthermore, we showed that specific brain factors that have been revealed to explain part of the individual variability to NIBS in young samples are also relevant in older adults. In accordance, designing multifocal tDCS configurations based on specific fMRI patterns appears to be a valuable approach to precisely adjust those complex neural dynamics sustaining cognition that are affected as a function of age. Furthermore, these innovative NIBS-based interventions should be individually-tailored based on subject-specific structural and functional data to ultimately boost their potential in aged populations.

neuroscience↗