Place field assembly distribution encodes preferred locations.

The hippocampus is the main locus of episodic memory formation and the neurons there encode the spatial map of the environment. Hippocampal place cells represent location, but their role in the learning of preferential location remains unclear. The hippocampus may encode locations independently from the stimuli and events that are associated with these locations. We have discovered a unique population code for the experience-dependent value of the context. The degree of reward-driven navigation preference highly correlates with the spatial distribution of the place fields recorded in the CA1 region of the hippocampus. We show place field clustering towards rewarded locations. Optogenetic manipulation of the ventral tegmental area demonstrates that the experience-dependent place field assembly distribution is directed by tegmental dopaminergic activity. The ability of the place cells to remap parallels the acquisition of reward context. Our findings present key evidence that the hippocampal neurons are not merely mapping the static environment but also store the concurrent context reward value, enabling episodic memory for past experience to support future adaptive behavior.

An open computational toolbox to analyze multi- and single-unit sympathetic nerve activity in microneurography.

Microelectrode recordings from human peripheral and cranial nerves provide a means to study both afferent and efferent axonal signals at different levels of detail, from multi- to single-unit activity. Their analysis can lead to advancements both in diagnostic and in the understanding of the genesis of neural disorders. However, most of the existing computational toolboxes for the analysis of microneurographic recordings are limited in scope or not open-source. Additionally, conventional burst-based metrics are not suited to analyze pathological conditions and are highly sensitive to distance of the microelectrode tip from the active axons. To address these challenges, we developed an open-source toolbox that offers advanced analysis capabilities for studying neuronal reflexes and physiological responses to peripheral nerve activity. Our toolbox leverages the observation of temporal sequences of action potentials within inherently cyclic signals, introducing innovative methods and indices to enhance analysis accuracy. Importantly, we have designed our computational toolbox to be accessible to novices in biomedical signal processing. This may include researchers and professionals in healthcare domains, such as clinical medicine, life sciences, and related fields. By prioritizing user-friendliness, our software application serves as a valuable resource for the scientific community, allowing to extract advanced metrics of neural activity in short time and evaluate their impact on other physiological variables in a consistent and standardized manner, with the final aim to widen the use of microneurography among researchers and clinicians.

Characterization of vagus nerve stimulation-induced pupillary responses in epileptic patients.

BACKGROUND: Modulation of the locus coeruleus (LC)-noradrenergic system is a key mechanism of vagus nerve stimulation (VNS). Activation of the LC produces pupil dilation, and the VNS-induced change in pupil diameter was demonstrated in animals as a possible dose-dependent biomarker for treatment titration. OBJECTIVE: This study aimed to characterize VNS-induced pupillary responses in epileptic patients. METHODS: Pupil diameter was recorded in ten epileptic patients upon four stimulation conditions: three graded levels of VNS intensity and a somatosensory control stimulation (cutaneous electrical stimulation over the left clavicle). For each block, the patients rated the intensity of stimulation on a numerical scale. We extracted the latency of the peak pupil dilation and the magnitude of the early (0-2.5 s) and late components (2.5-5 s) of the pupil dilation response (PDR). RESULTS: VNS elicited a peak dilation with longer latency compared to the control condition (p = 0.043). The magnitude of the early PDR was significantly correlated with the intensity of perception (p = 0.046), whereas the late PDR was not (p = 0.19). There was a significant main effect of the VNS level of intensity on the magnitude of the late PDR (p = 0.01) but not on the early PDR (p = 0.2). The relationship between late PDR magnitude and VNS intensity was best fit by a Gaussian model (inverted-U). CONCLUSIONS: The late component of the PDR might reflect specific dose-dependent effects of VNS, as compared to control somatosensory stimulation. The inverted-U relationship of late PDR with VNS intensity might indicate the engagement of antagonist central mechanisms at high stimulation intensities.

Chronic recording of the vagus nerve to analyze modulations by the light-dark cycle.

Objective.The vagus nerve is considered to play a key role in the circadian rhythm. Chronic continuous analysis of the vagus nerve activity could contribute to a better understanding of the role of the vagus nerve in light-dark modulations. This paper presents a continuous analysis of spontaneous vagus nerve activity performed in four rats.Approach.We analyzed the vagus electroneurogram (VENG) and electroencephalogram (EEG) over a recording period of 28 d. Spike activity and heart rate estimation were derived from the VENG, and slow-wave activity was derived from the EEG. The presence of repetitive patterns was investigated with periodograms, cosinor fitting, autocorrelation, and statistical tests. The light-dark variations derived from the VENG spikes were compared with EEG slow waves, an established metric in circadian studies.Results.Our results demonstrate that light-dark variations can be detected in long-term vagus nerve activity monitoring. A recording period of about 7 d is required to characterize accurately the VENG light-dark variations.Significance.As a major outcome of this study, vagus nerve recordings hold the promise to help understand circadian regulation.

Vagus Nerve Electroneurogram-Based Detection of Acute Pentylenetetrazol Induced Seizures in Rats.

On-demand stimulation improves the efficacy of vagus nerve stimulation (VNS) in refractory epilepsy. The vagus nerve is the main peripheral parasympathetic connection and seizures are known to exhibit autonomic symptoms. Therefore, we hypothesized that seizure detection is possible through vagus nerve electroneurogram (VENG) recording. We developed a metric able to measure abrupt changes in amplitude and frequency of spontaneous vagus nerve action potentials. A classifier was trained using a "leave-one-out" method on a set of 6 seizures and 3 control recordings to utilize the VENG spike feature-based metric for seizure detection. We were able to detect pentylenetetrazol (PTZ) induced acute seizures in 6/6 animals during different stages of the seizure with no false detection. The classifier detected the seizure during an early stage in 3/6 animals and at the onset of tonic clonic stage of the seizure in 3/6 animals. EMG and motion artefacts often accompany epileptic activity. We showed the "epileptic" neural signal to be independent from EMG and motion artefacts. We confirmed the existence of seizure related signals in the VENG recording and proved their applicability for seizure detection. This detection might be a promising tool to improve efficacy of VNS treatment by developing new responsive stimulation systems.

Vagus Nerve Stimulation Elicits Sleep EEG Desynchronization and Network Changes in Responder Patients in Epilepsy.

Neural desynchronization was shown as a key mechanism of vagus nerve stimulation (VNS) action in epilepsy, and EEG synchronization measures are explored as possible response biomarkers. Since brain functional organization in sleep shows different synchrony and network properties compared to wakefulness, we aimed to explore the effects of acute VNS on EEG-derived measures in the two different states of vigilance. EEG epochs were retrospectively analyzed from twenty-four VNS-treated epileptic patients (11 responders, 13 non-responders) in calm wakefulness and stage N2 sleep. Weighted Phase Lag Index (wPLI) was computed as connectivity measure of synchronization, for VNS OFF and VNS ON conditions. Global efficiency (GE) was computed as a network measure of integration. Ratios OFF/ON were obtained as desynchronization/de-integration index. Values were compared between responders and non-responders, and between EEG states. ROC curve and area-under-the-curve (AUC) analysis was performed for response classification. In responders, stronger VNS-induced theta desynchronization (p < 0.05) and decreased GE (p < 0.05) were found in sleep, but not in wakefulness. Theta sleep wPLI Ratio OFF/ON yielded an AUC of 0.825, and 79% accuracy as a response biomarker if a cut-off value is set at 1.05. Considering all patients, the VNS-induced GE decrease was significantly more important in sleep compared to awake EEG state (p < 0.01). In conclusion, stronger sleep EEG desynchronization in theta band distinguishes responders to VNS therapy from non-responders. VNS-induced reduction of network integration occurs significantly more in sleep than in wakefulness.

Infrared neurostimulation inex-vivorat sciatic nerve using 1470 nm wavelength.

Objective.To design and implement a setup forex-vivooptical stimulation for exploring the effect of several key parameters (optical power and pulse duration), activation features (threshold, spatial selectivity) and recovery characteristics (repeated stimuli) in peripheral nerves.Approach.A nerve chamber allowing ex-vivo electrical and optical stimulation was designed and built. A 1470 nm light source was chosen to stimulate the nerve. A photodiode module was implemented for synchronization of the electrical and optical channels.Main results. Compound neural action potentials (CNAPs) were successfully generated with infrared light pulses of 200-2000µs duration and power in the range of 3-10 W. These parameters determine a radiant exposure for stimulation in the range 1.59-4.78 J cm-2. Recruitment curves were obtained by increasing durations at a constant power level. Neural activation threshold is reached at a mean radiant exposure of 3.16 ± 0.68 J cm-2and mean pulse energy of 3.79 ± 0.72 mJ. Repetition rates of 2-10 Hz have been explored. In eight out of ten sciatic nerves (SNs), repeated light stimuli induced a sensitization effect in that the CNAP amplitude progressively grows, representing an increasing number of recruited fibres. In two out of ten SNs, CNAPs were composed of a succession of peaks corresponding to different conduction velocities.Significance.The reported sensitization effect could shed light on the mechanism underlying infrared neurostimulation. Our results suggest that, in sharp contrast with electrical stimuli, optical pulses could recruit slow fibres early on. This more physiological order of recruitment opens the perspective for specific neuromodulation of fibre population who remained poorly accessible until now. Short high-power light pulses at wavelengths below 1.5µm offer interesting perspectives for neurostimulation.

Analysing vagus nerve spontaneous activity using finite element modelling.

Objective.Finite element modelling has been widely used to understand the effect of stimulation on the nerve fibres. Yet the literature on analysis of spontaneous nerve activity is much scarcer. In this study, we introduce a method based on a finite element model, to analyse spontaneous nerve activity with a typical bipolar electrode recording setup, enabling the identification of spontaneously active fibres. We applied our method to the vagus nerve, which plays a key role in refractory epilepsy.Approach.We developed a 3D model including dynamic action potential (AP) propagation, based on the vagus nerve geometry. The impact of key recording parameters-inter-electrode distance and temperature-and uncontrolled parameters-fibre size and position in the nerve-on the ability to discriminate active fibres were quantified. A specific algorithm was implemented to detect and classify APs from recordings, and tested on six ratin-vivovagus nerve recordings.Main results.Fibre diameters can be discriminated if they are below 3µm and 7µm, respectively for inter-electrode distances of 2 mm and 4 mm. The impact of the position of the fibre inside the nerve on fibre diameter discrimination is limited. The range of active fibres identified by modelling in the vagus nerve of rats is in agreement with ranges found at histology.Significance.The nerve fibre diameter, directly proportional to the AP propagation velocity, is related to a specific physiological function. Estimating the source fibre diameter is thus essential to interpret neural recordings. Among many possible applications, the present method was developed in the context of a project to improve vagus nerve stimulation therapy for epilepsy.

Recording of spontaneous vagus nerve activity during Pentylenetetrazol-induced seizures in rats.

BACKGROUND: Vagus nerve stimulation is a treatment for refractory epilepsy. The vagus nerve carries parasympathetic information and innervates multiple organs. As seizures are commonly associated with autonomic manifestations, we believe that biomarkers for diseases affecting autonomic functions such as epilepsy can be found in vagus nerve signals. NEW METHOD: We present a method to record vagus nerve electroneurogram (VENG) and detect in the VENG single unit activity in anesthetized rats during Pentylenetetrazol induced seizures using a true tripolar cuff electrode. RESULTS: The VENG consisted of high amplitude bursts and lower amplitude bursts synchronous to respiration and heartbeat respectively. The average spikes exhibited a triphasic shape with duration below 1.5ms and root mean square amplitude varied between 5.5 +/- 0.2 µV and 11.4 +/- 3.1 µV depending on the type of recording. An increase of the contact distance resulted in a signal amplitude increase. Application of Lidocaine led to a total disappearance of the recorded spontaneous spiking of the nerve. COMPARISON WITH EXISTING METHODS: True tripolar cuff electrodes exhibited a better performance in terms of artefact rejection, stability and reproducibility of the signal compared to commonly used hook electrodes which is of special interest in seizures where important motion and EMG artifacts are expected. CONCLUSION: We present a new method to record single unit activity of the vagus nerve during acute chemically induced seizures in rats and verified the neural origin of the recorded signals. This recording method might be a powerful tool to develop seizure biomarkers based on VENG.

Extrafield Activity Shifts the Place Field Center of Mass to Encode Aversive Experience.

Hippocampal place cells are known to have a key role in encoding spatial information. Aversive stimuli, such as predator odor, evoke place field remapping and a change in preferred firing locations. However, it remains unclear how place cells use positive or negative experiences to remap. We investigated whether CA1 place cells, recorded from behaving rats, remap randomly or whether their reconfiguration depends on the perceived location of the aversive stimulus. Exposure to trimethylthiazoline (TMT; an innately aversive odor), increased the amplitude of hippocampal ß oscillations in the two arms of the maze in which TMT exposure occurred. We found that a population of place cells with fields located outside the TMT arms increased their activity (extrafield spiking) in the TMT arms during the aversive episodes. Moreover, in the subsequent post-TMT recording, these cells exhibited a significant shift in their center of mass (COM) towards the TMT arms. The induction of extrafield plasticity was mediated by the basolateral amygdala complex (BLA). Photostimulation of the BLA triggered aversive behavior, synchronized hippocampal local field oscillations, and increased the extrafield spiking of the hippocampal place cells for the first 100 ms after light delivery. Optogenetic BLA activation triggered an increase in extrafield spiking activity that was correlated with the degree of place field plasticity. Furthermore, BLA-mediated increase of the extrafield activity predicts the degree of subsequent field plasticity. Our findings demonstrate that that the remapping of hippocampal place cells during aversive episodes is not random but it depends on the location of the aversive stimulus.

Vagus Nerve Stimulation-Induced Laryngeal Motor Evoked Potentials: A Possible Biomarker of Effective Nerve Activation.

Vagus nerve stimulation (VNS) therapy is associated with laryngeal muscle activation and induces voice modifications, well-known side effects of the therapy resulting from co-activation of the recurrent laryngeal nerve. In this study, we describe the non-invasive transcutaneous recording of laryngeal motor evoked potentials (LMEPs), which could serve as a biomarker of effective nerve activation and individual titration in patients with drug-resistant epilepsy. We recruited drug-resistant epileptic patients treated for at least 6 months with a VNS. Trains of 600-1200 VNS pulses were delivered with increasing current outputs. We placed six skin electrodes on the ventral surface of the neck, in order to record LMEPs whenever the laryngeal muscular threshold was reached. We studied the internal consistency and the variability of LMEP recordings, and compared different methods for amplitude calculation. Recruitment curves were built based on the stimulus-response relationship. We also determined the electrical axis of the LMEPs dipole in order to define the optimal electrode placement for LMEPs recording in a clinical setting. LMEPs were successfully recorded in 11/11 patients. The LMEPs threshold ranged from 0.25 to 1 mA (median 0.50 mA), and onset latency was between 5.37 and 8.77 ms. The signal-to-noise ratio was outstanding in 10/11 patients. In these cases, excellent reliability (Intraclass correlation coefficient, ICC > 0.90 across three different amplitude measurements) was achieved with 10 sample averages. Moreover, our recordings showed very good internal consistency (Cronbach's alpha > 0.95 for 10 epochs). Area-under-the-curve and peak-to-peak measurement proved to be complementary methods for amplitude calculation. Finally, we determined that an optimal derivation requires only two recording electrodes, aligned on a horizontal axis around the laryngeal prominence. In conclusion, we describe here an optimal methodology for the recording of VNS-induced motor evoked responses from the larynx. Although further clinical validation is still necessary, LMEPs might be useful as a non-invasive marker of effective nerve activation, and as an aid for the clinician to perform a more rational titration of VNS parameters.