Biology subjects

Fedele, T.

Publications and source records attributed to Fedele, T..

5 recordsLinked to original sources

bioRxiv2024

Network models incorporating chloride dynamics predict optimal strategies for terminating status epilepticus

Seizures that continue for beyond five minutes are classified as status epilepticus (SE) and constitute a medical emergency. Benzodiazepines, the current first-line treatment, attempt to terminate SE by increasing the conductance of chloride-permeable type-A GABA receptors (GABAARs). Despite their widespread use, benzodiazepines are ineffective in over a third of cases. Previous research in animal models has demonstrated that changes in intraneuronal chloride homeostasis and GABAAR physiology may underlie the development of benzodiazepine resistance in SE. However, there remains a need to understand the effect of these changes at a network level to improve translation into the clinical domain. Therefore, informed by data from human EEG recordings of SE and experimental brain slice recordings, we used a large spiking neural network model that incorporates chloride dynamics to investigate and address the phenomenon of benzodiazepine resistance in SE. We found that the GABAAR reversal potential (EGABA) sets SE-like bursting and determines the response to GABAAR conductance modulation, with benzodiazepines being anti-seizure at low EGABA and ineffective or pro-seizure at high EGABA. The SE-like activity and EGABA depended on a non-linear relationship between the strength of Cl- extrusion and GABAAR conductance, but not on the initial EGABA of neurons. Independently controlling Cl- extrusion in the pyramidal and interneuronal cell populations revealed the critical role of pyramidal cell Cl- extrusion in determining the severity of SE activity and the response to simulated benzodiazepine application. Finally, we demonstrate the models utility for considering improved therapeutic approaches for terminating SE in the clinic.

neuroscience↗

bioRxiv2022

Auditory prediction hierarchy in the human hippocampus and amygdala

Our brains can extract structure from the environment and form predictions given past sensory experience. Predictive circuits have been identified in wide-spread cortical regions. However, the contribution of subcortical areas, such as the hippocampus and amygdala in the formation of predictions remains under-explored. Here, we hypothesized that the hippocampus would be sensitive to predictability in sound sequences, while the amygdala would be sensitive to unexpected violations of auditory rules. We presented epileptic patients undergoing presurgical monitoring with standard and deviant sounds, in a predictable or unpredictable context. Onsets of auditory responses and unpredictable deviance effects were detected at earlier latencies in the temporal cortex compared to the amygdala and hippocampus. Deviance effects in 1-20 Hz local field potentials were detected in the lateral temporal cortex, irrespective of predictability. The amygdala showed stronger deviance responses in the unpredictable context. Additionally, low frequency deviance responses in the hippocampus (1-8 Hz) were observed in the predictable but not in the unpredictable context. Our results reveal a distributed cortical-subcortical network underlying the generation of auditory predictions, comprising temporal cortex and the hippocampus and amygdala, and suggest that the neural basis of sensory predictions and prediction error signals needs to be extended to subcortical regions.

neuroscience↗

bioRxiv2022

Changes in oscillations in anterior cingulate and medial prefrontal cortex are associated with altered signatures of Bayesian predictive coding in trait anxiety

Recent advances in the computational understanding of decision-making processes have led to proposals that anxiety biases how individuals form beliefs and estimate uncertainty. The anxiety and decision-making circuitry broadly overlap in regions such as the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). Changes in activity across these brain areas could help explain how misestimation of uncertainty and altered belief updating can lead to impaired learning in anxiety. To test this prediction, this study built on recent progress in rhythm-based formulations of Bayesian predictive coding to identify sources of oscillatory modulations across the ACC, mPFC, and OFC that are associated with altered learning in subclinical trait anxiety. In a magnetoencephalography (MEG) experiment, two groups of human participants pre-screened with high and low trait anxiety (HTA, LTA: 39) performed a volatile probabilistic reward-based learning task. We modelled behaviour using a hierarchical Bayesian learning model. Furthermore, we quantified the parametric effects of trial-wise estimates of unsigned precision-weighted prediction errors (pwPEs) and, separately, precision weights and surprise on source-reconstructed MEG time-frequency responses using convolution modelling. We showed that HTA interferes with overall reward-based learning performance associated with more stochastic decisions and more pronounced lose-shift tendencies. These behavioural effects were explained by an overestimation of volatility and faster belief updating in HTA when compared to LTA. On a neural level, we observed enhanced gamma responses and decreased alpha/beta activity in HTA during the encoding of unsigned pwPEs about about stimulus outcomes relative to LTA. These effects emerged primarily in the ACC and dorsomedial PFC (dmPFC), and they were accompanied by additional ACC alpha/beta modulations representing differential encoding of precision weights in each anxiety group. Our study supports the association between subclinical trait anxiety and faster updating of beliefs in a volatile environment through gamma and alpha/beta activity changes in the ACC and dmPFC.

neuroscience↗

bioRxiv2022

The influence of learning on robustness of working memory to distractors

Inhibition of irrelevant information is a crucial process within the working memory (WM) system. In the present study, we explored how inhibition of distractors is learned within a Sternberg-like WM task and how this learning process affects readout performance. We introduced distractors of varying strength as well as novel stimuli to a classic Sternberg task. Our findings show that the length of the training period affected obstructiveness of distractors as well as differences between WM loads. Significant differences between conditions observed early on in accuracy became void after general ceiling performance was reached. Moreover, accuracy and reaction times, which are commonly used as readouts of WM performance, were affected differently by training. While both improved significantly, only accuracy exhibited differential dependency of experimental conditions on training. It is essential to consider these dynamics when introducing a WM task which requires a long training period.

neuroscience↗

bioRxiv2016

RL mechanisms of short-term plasticity of auditory cortex

The decision-making process is exposed to modulatory factors, and, according to the expected value (EV) concept the two most influential factors are magnitude of prospective behavioural outcome and probability of receiving this outcome. The discrepancy between received and predicted outcomes is reflected by the reward prediction error (RPE), which is believed to play a crucial role in learning in dynamic environment. Feedback related negativity (FRN), a frontocentral negative component registered in EEG during feedback presentation, has been suggested as a neural signature of RPE. In modern neurobiological models of decision-making the primary sensory input is assumed to be constant over the time and independent of the evaluation of the option associated to it. In this study we investigated whether the electrophysiological changes in auditory cues perception is modulated by the strengths of reinforcement signal, represented in the EEG as FRN.\n\nWe quantified the changes in sensory processing through a classical passive oddball paradigm before and after performance a neuroeconomic monetary incentive delay (MID) task. Outcome magnitude and probability were encoded in the physical characteristics of auditory incentive cues. We evaluated the association between individual biomarkers of reinforcement signal (FRN) and the degree of perceptual learning, reflected by changes in auditory ERP components (mismatch negativity and P3a). We observed a significant correlation of MMN and valence - dFRN, reflecting differential processing of gains and omission of gains. Changes in P3a were correlated to probability - dFRN, including information on salience of the outcome, in addition to its valence.\n\nMID task performance evokes plastic changes associated with more fine-grained discrimination of auditory anticipatory cues and enhanced involuntary attention switch towards these cues. Observed signatures of neuro-plasticity of the auditory cortex may play an important role in learning and decision-making processes through facilitation of perceptual discrimination of valuable external stimuli. Thus, the sensory processing of options and the evaluation of options are not independent as implicitly assumed by the modern neuroeconomics models of decision-making.

neuroscience↗