Biology subjects

Hernadi, I.

Publications and source records attributed to Hernadi, I..

12 recordsLinked to original sources

bioRxiv2026

Transcranial Magnetic Stimulation in Awake Rhesus macaques: Validation of a Novel Non-invasive Apparatus

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique widely employed in basic and clinical research. Non-human primates (NHPs) represent translationally valuable models due to their close anatomical and functional similarity to humans. However, significant technical challenges remain in implementing human-like TMS protocols in awake NHPs. Here we developed a non-invasive head- and arm-fixation apparatus that enables reliable stimulation and electromyography recordings in awake NHPs without surgical intervention and validated the apparatus with two TMS protocols in rhesus macaques. First, we implemented an adaptive motor threshold (MT) determination method developed recently for humans, which converged successfully to valid MTs as defined by the International Federation of Clinical Neurophysiology. Second, we measured a robust short-interval intracortical inhibition effect for the first time in awake NHPs. Successful implementation of human TMS protocols in awake NHPs provides proof-of-concept validation of our apparatus, paving the way to bidirectionally translatable, clinically relevant neuromodulation protocols.

neuroscience↗

bioRxiv2025

CoreTIA: a modular, statistically robust transduction inhibition assay for AAV neutralization

Adeno-associated virus (AAV) gene therapy is often limited by pre-existing neutralizing antibodies (NAbs), yet current assays for NAb detection lack standardization and rarely quantify uncertainty, complicating cross-study comparisons. We present coreTIA (core Transduction Inhibition Assay), a modular experimental protocol combined with a statistically robust analysis pipeline that delivers precise, reproducible NAb titers with quantified uncertainty for every result. coreTIAs statistical framework enables robust estimation of neutralization even when dilution series are incomplete, helping to reduce repeat testing and minimizing sample volume requirements. Evaluation and refinement of key assay parameters support consistent performance across AAV serotypes. By providing a protocol and analysis suite as an open resource, coreTIA facilitates more consistent and transparent NAb measurement, potentially aiding assay harmonization and regulatory assessment, addressing a key barrier to progress in gene therapy research and development.

immunology↗

bioRxiv2024

Assessment of cortical excitability in awake rhesus macaques with transcranial magnetic stimulation: translational insights from recruitment curves

Background and objectivesCortical excitability (CE) is commonly assessed by recording motor evoked potentials (MEPs) in response to single-pulse transcranial magnetic stimulation (sp-TMS). While the motor threshold (MT) remains the most widely used measure of CE, it provides a one-dimensional, criterion-based assessment. In contrast, the recruitment curve (RC) offers a more comprehensive characterization of the full dynamics of cortical recruitment. Yet, only a few preclinical studies involving translationally relevant non-human primates were conducted, and most were under anaesthesia. Hence, we aimed to characterise CE in awake rhesus macaques by recording traditionally defined MT and RCs. MethodsTraditional MT with a 100 {micro}V MEP criterion ( tradMT) was measured in 8 awake adult male rhesus macaques using C-B65 coil and MagVenture stimulator. RCs were recorded at nine relative intensity levels (0.5 - 1.5 x tradMT) in 4 macaques. A sigmoid function was fitted to obtain key CE parameters: the inflection point, lower ankle point, and plateau. ResultsTradMT values were stable and replicable, and aligned most closely with the inflection point of the RC. The lower ankle points were found around at 0.9 x tradMT, marking the transition from a constant to a logarithmic phase, representing a physiologically relevant threshold. Plateau MEP amplitudes were substantially smaller compared to those reported in humans. ConclusionFitted RC parameters revealed a distinction between tradMT and the physiologically relevant threshold. The overall RC shape was consistent with human data, suggesting similar recruitment processes, leading to high translational validity. However, the marked difference in maximal MEP magnitude emphasises the importance of species-specific adaptations.

neuroscience↗

bioRxiv2024

GLP-1 receptor agonist exenatide uncouples food intake from hedonic and anticipatory regulation in non-human primates: Insights from an operant meal schedule paradigm

Glucagon-like peptide 1 (GLP-1), a neuroendocrine signal of energy balance and satiety, has a major role in regulating food intake behaviour. Here we investigated the effects of the GLP-1 agonist exenatide on palatability-driven feeding regulation in adult male rhesus macaques (n=5) using a novel operant food intake paradigm with four meal schedule conditions where two types of pellets with different palatability values were offered as meal in all combinations in two consecutive daily feeding sessions (S1 and S2). In control conditions, a strong, palatability-driven anticipatory effect was found in S1, followed by a complementary positive contrast effect in S2. After acute subcutaneous treatment with 1 {micro}g/kg dose of exenatide 1 h before S1, food intake decreased to the same very low level in all meal schedule conditions in S1, completely erasing the previously observed anticipatory effect. Conversely, exenatide induced hypoglycaemia in an anticipatory meal schedule dependent pattern. Interestingly, the previously observed positive contrast effect was spared in S2, with a weaker residual effect specifically on the consumption of the more palatable pellet type. To conclude, the food intake reducing effects of exenatide may temporally evolve from strong anorectic to weak anhedonic modulations, where hedonic experience and anticipation during the early anorectic phase is conserved but uncoupled from food intake behaviour.

pharmacology and toxicology↗

bioRxiv2023

Combination of memantine and alpha7 nicotinic acetylcholine receptor ligands exerts superior efficacy over monotreatments to improve cognitive performance of aged rats

Combination treatments based on pharmacological interactions at 7 nAChRs are promising therapeutic approaches for neurocognitive disorders (NCDs). Memantine, an already approved medication in some NCDs, may not only act as an antagonist of the glutamatergic NMDA receptors (NMDAR) but also serve as an antagonist of the cholinergic 7 nAChRs. Here we set out to utilize a combination treatment regime with an 7 nAChR-selective agonist (PHA-543613) and a novel proprietary 7 nAChR ligand with marked positive allosteric modulator (PAM) activity (CompoundX). The cognitive efficacy of combination treatments was tested in a naturally aged rat model. Naturally aged rats showed marked cognitive decline in the novel object recognition (NOR) test, and they displayed pathological changes at the molecular level in terms of various inflammatory markers. In addition, aged rats also exhibited cholinergic changes such as mRNA upregulation of 7 nAChRs. Memantine-PHA-543613 and memantine-CompoundX combination treatments successfully alleviated the age-related decline of recognition memory of rats by exceeding the null-effects of the corresponding subtherapeutic levels of monotreatments. Results indicate a positive interaction between memantine and 7-nAChR agonists and PAMs, which reflects a prominent role of 7 nAChRs in the cognitive enhancement of combination treatments especially in age-related cognitive decline. Moreover, the putative direct action of memantine on 7 nAChRs may also contribute to the observed synergistic interaction between memantine and other selective 7 nAChR compounds.

pharmacology and toxicology↗

bioRxiv2022

Traumatic brain injury induced microglial and Caspase3 activation in the retina

Traumatic brain injury (TBI) is among the main causes of sudden death after head trauma. These injuries can result in severe degeneration and neuronal cell death in the CNS, including the retina which is a crucial part of the brain responsible for perceiving and transmitting visual information. The long-term effects of mild-repetitive TBI (rmTBI) are far less studied thus far, even though damages induced by repetitive injuries occurring in the brain are more common, especially amongst athletes. rmTBI can also have a detrimental effect on the retina and the pathophysiology of these injuries are likely to differ from the severe TBI (sTBI) retinal injury. Here we showed how rmTBI and sTBI can dissimilarly affect the retina. Our results indicate an increase in the number of activated microglial cells and Caspase3-positive cells in the retina in both traumatic models, suggesting a rise in the level of inflammation and cell death after TBI. The pattern of microglial activation appears evenly distributed and widespread but differs amongst the various retinal layers. sTBI induced microgial activation in both the superficial and deep retinal layers. In contrast to sTBI, no significant change occurred following the repetitive mild injury in the superficial layer, only the deep layer (spanning from the inner nuclear layer to the outer plexiform layer) shows microglial activation. This difference suggests that alternate response mechanisms play a role in the case of the different TBI incidents. The Caspase3 activation pattern showed a uniform increase in both the superficial and deep layers of the retina. This suggests a different action in the course of the disease in sTBI and rmTBI models and points to the need for new diagnostic procedures. Our present results suggest that the retina might serve as such a model of head injuries since the retinal tissue reacts to both forms of TBI and is the most accessible part of the human brain.

neuroscience↗

bioRxiv2020

Low Physiological Arousal in Mental Fatigue: Analysis of Heart Rate Variability during Time-on-task, Recovery, and Reactivity

Heart Rate Variability (HRV) has been suggested as a useful tool to assess fatigue-sensitive psychological operations. The present study uses between and within-subject design to examine the temporal profile of HRV including the changes related to reactivity, time-on-task (ToT), and recovery on a cognitively demanding task. In the fatigue group, participants worked on a bimodal 2-back task with a game-like character (the gatekeeper task) for about 1.5 hours, followed by a 12-minute break, and a post-break block of performance (about 18 min). In the control group, participants watched documentaries. We hypothesized that mental fatigue is associated with low physiological arousal and increasing vagal-mediated HRV as a function of ToT. We also analysed the trial-based post-response cardiac activity as a physiological indicator of task-related motivation. Relative to the control, ToT was associated with an elevated level of subjective fatigue, decreased heart rate, and increased HRV most robustly in the vagal-mediated components. Based on fatigued participants post-error cardiac slowing, and post-error reaction time analyses, we found no evidence for motivation deficit in association with increasing HRV and ToT. The present findings support the low arousal state of mental fatigue and suggest that primarily the vagal components of the HRV spectrum are indicative of fatigue. In addition, the study provides evidence that many HRV indices might be changed not only in a fatiguing condition but also if individuals are engaged in a prolonged non-fatiguing activity. This finding emphasizes the relevance of control conditions in ToT experiments.

neuroscience↗

bioRxiv2020

Delay-dependent cholinergic modulation of visual short-term memory in rhesus macaques

Cholinergic neuromodulation is known to play a key role in visual working memory (VWM) - keeping relevant stimulus representations available for cognitive processes for short time periods up to a few minutes. Despite the growing body of evidence on how the neural and cognitive mechanisms of VWM dynamically change over retention time, there is mixed evidence available on cholinergic effects as a function of VWM delay period in non-human primates. Using the delayed matching to sample VWM task in rhesus macaques (N=6), we aimed to characterize VWM maintenance in terms of performance changes as a function of delay duration (across a wide range of delays from 1 to 76 s). Then, we studied how cholinergic neuromodulation influences VWM maintenance using the muscarinic receptor antagonist scopolamine administered alone as transient amnestic treatment, and in combination with two doses of the acetylcholinesterase inhibitor donepezil, a widely used Alzheimers medication probing for the reversal of scopolamine-induced impairments. Results indicate that scopolamine-induced impairments of VWM maintenance are delay-dependent and specifically affect the 15-33 s time range, suggesting that scopolamine worsens the normal decay of VWM with the passage of time. Donepezil partially rescued the observed scopolamine-induced impairments of VWM performance. These results provide strong behavioral evidence for the role of increased cholinergic tone and muscarinic neuromodulation in the maintenance of VWM beyond a few seconds, in line with our current knowledge on the role of muscarinic acetylcholine receptors in sustained neural activity during VWM delay periods.

animal behavior and cognition↗

bioRxiv2019

Dissociating cholinergic influence on alertness andtemporal attention in primates in a simple reaction-timeparadigm

The ability to promptly respond to behaviourally relevant events depends on both general alertness and phasic changes in attentional state driven by temporal expectations. Using a variable foreperiod simple reaction time (RT) task in four adult male rhesus macaques, we investigated the role of the cholinergic system in alertness and temporal expectation. Foreperiod-effects on RT reflect temporal expectation, while alertness is quantified as overall response speed. We measured these RT parameters under vehicle treatment and systemic administration of the muscarinic receptor antagonist scopolamine. We also investigated whether and to what extent the effects of scopolamine were reversed by donepezil, a cholinesterase inhibitor widely used for the treatment of dementia. In the control condition, RT showed a continuous decrease as the foreperiod duration increased, which clearly indicated the effect of temporal expectation on RT. This foreperiod effect was mainly detectable on the faster tail of the RT distribution and was eliminated by scopolamine. Furthermore, scopolamine treatment slowed down the average RT. Donepezil treatment was efficient on the slower tail of the RT distribution and improved scopolamine-induced impairments only on the average RT reflecting a general beneficial effect on alertness without any improvement in temporal expectation. The present results highlight the role of the cholinergic system in temporal expectation and alertness in primates and help delineate the efficacy and scope of donepezil and other cholinomimetic agents as cognitive enhancers in present and future clinical practice.

animal behavior and cognition↗

bioRxiv2019

Long-term persistence of cognitive impairment following repetitive mild traumatic brain injury in rats is not associated with common histopathological or molecular biomarkers

Repetitive mild traumatic brain injuries (TBI) impair cognitive abilities and increase risk of neurodegenerative disorders in humans. We developed two repetitive mild TBI models in rats with different time intervals between successive weight-drop injuries, and assessed cognitive performance and biomarker profiles. Rats were subjected to repetitive Sham (no injury), single mild (mTBI), repetitive mild (rmTBI - 5 hits, 24 h apart), rapid repetitive mild (rapTBI - 5 hits, 5 min apart) and single severe (sTBI) TBI. We assessed cognitive performance 2 and 8 weeks after TBI in the novel object recognition test (NOR), and 6-7 weeks after TBI in the water maze (MWM). Acute immunohistochemical markers were checked 24 h after TBI, and blood biomarkers were measured with ELISA 8 weeks after TBI. In the NOR, both rmTBI and rapTBI showed poor performance at 2 weeks post-injury. At 8 weeks post-injury, the rmTBI group still performed worse than the Sham and mTBI groups, while the rapTBI group recovered. In the MWM, the rapTBI group performed worse than Sham and mTBI. Acute APP and RMO-14 immunohistochemistry showed axonal injury at the pontomedullary junction in the sTBI, but not in other groups. ELISA showed increased serum GFAP levels 8 weeks after sTBI, while no differences were found between the injury groups in the levels of phosphorylated-tau and S100{beta}. Results suggest that the rmTBI protocol is the most suitable model for testing cognitive impairment after mild repetitive head injuries. The lack of common biomarkers suggests novel unknown underlying mechanisms of rmTBI.

neuroscience↗

bioRxiv2019

Facilitation and inhibition of firing activity and N-methyl-D-aspartate-evoked responses of CA1 hippocampal pyramidal cells by alpha7 nicotinic acetylcholine receptor selective compounds in vivo

Alpha7 nicotinic acetylcholine receptors (nAChRs) are promising novel targets for the treatment of neurocognitive disorders. Although the cognitive enhancer potential of alpha7 nAChR agonists and positive allosteric modulators (PAMs) has been confirmed in several preclinical animal models, there are only sparse in vivo electrophysiological data on their effects on the firing activity and excitability of neurons. The present study investigated and compared local effects of alpha7 nAChR agonist PHA-543613 and PAMs PNU-120596 and NS-1738 on the spontaneous and N-methyl-D-aspartate-evoked (NMDA-evoked) firing rate of rat CA1 hippocampal pyramidal cells, in vivo. Furthermore, effects of alpha7 nAChR antagonist methyllycaconitine (MLA) and GABA were also tested. Results showed substantially different effects of the alpha7 nAChR agonist and PAMs. While PNU-120596 and NS-1738 predominantly and significantly increased both spontaneous and NMDA-evoked firing rate of the neurons, application of PHA-543613 resulted in almost equal distribution of facilitatory and inhibitory effects. The increase of the NMDA-evoked firing rate exerted by NS-1738 was superadditive over the sum of the single effects of NMDA and NS-1738. The simultaneous application of alpha7 nAChR agonist PHA-543613 and PAM NS-1738 resulted in additive increase of both spontaneous and NMDA-evoked firing rate. However, NS-1738 counteracted inhibitory effects of PHA-543613 in 5 out of 6 neurons, resulting in a synergistic potentiation of their firing responses to NMDA. Our results suggest that alpha7 nAChR PAMs increase neuronal excitability more potently than agonists, while the remarkable occurrence of inhibitory effects of PHA-543613 (possibly originating from receptor desensitization) implies that agonists may exert neuroprotective effects.

neuroscience↗

bioRxiv2018

Short-term radiofrequency exposure from new generation mobile phones reduces EEG alpha power with no effects on cognitive performance

Although mobile phone (MP) use has been steadily increasing in the last decades and similar positive trends are expected for the near future, systematic investigations on neurophysiological and cognitive effects caused by recently developed technological standards for MPs are scarcely available. Here, we investigated the effects of radiofrequency (RF) fields emitted by new-generation mobile technologies, specifically, Universal Mobile Telecommunications System (UMTS) and Long-Term Evolution (LTE), on intrinsic scalp EEG activity in the alpha band (8-12 Hz) and cognitive performance in the Stroop test. The study involved 60 healthy, young-adult university students (34 for UMTS and 26 for LTE) with double-blind administration of Real and Sham exposure in separate sessions. EEG was recorded before, during and after RF exposure, and Stroop performance was assessed before and after EEG recording. Both RF exposure types caused a notable decrease in the alpha power over the whole scalp that persisted even after the cessation of the exposure, whereas no effects were found on any aspects of performance in the Stroop test. The results imply that the brain networks underlying global alpha oscillations might require minor reconfiguration to adapt to the local biophysical changes caused by focal RF exposure mimicking MP use.

neuroscience↗