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The objective of the study was to record Laryngeal Motor Evoked Potentials (LMEPs) in Vagus Nerve Stimulation (VNS)-implanted patients suffering from Drug-Resistant Epilepsy (DRE). Based on these recordings, LMEPs characteristics were evaluated and compared between responders (R) and non-responders (NR). Finally, possible under- or over-stimulation was assessed based on a physiological indicator of fiber engagement. Methods: Mean dose–response curves were compared between R and NR. A Support Vector Machine (SVM) model was built based on both LMEP and dose–response curves features, to discriminate R from NR. For the exploration of possible under- or over-stimulation, a ratio between the clinically applied stimulation intensity and the intensity yielding to LMEP saturation was computed for each patient. Results: A trend towards a greater excitability of the nerve was observed in R compared to NR. The SVM classifier discriminated R and NR with an accuracy of 80%. An ineffective attempt to overstimulate at current levels above what is usually necessary to obtain clinical benefits was suggested in NR. Conclusions: The SVM model built emphasizes a possible link between vagus nerve recruitment characteristics and treatment effectiveness. Most of the clinically responding patients receive VNS at a stimulation intensity 1-fold and 2-fold the intensity inducing LMEP saturation. Significance: LMEP saturation could be a practical help in guiding the titration of the stimulation parameters using a physiological indicator of fiber engagement.

AimsThe blue light-sensitive chloride-conducting opsin, stGtACR2, provides potent optogenetic silencing of neurons. The present study investigated whether activation of stGtACR2 in granule cells of the dentate gyrus (DG) inhibits epileptic afterdischarges in a rat model. MethodsRats were bilaterally injected with 0.9 mu l of AAV2/7-CaMKII alpha-stGtACR2-fusionred in the DG. Three weeks later, afterdischarges were recorded from the DG by placing an optrode at the injection site and a stimulation electrode in the perforant path (PP). Afterdischarges were evoked every 10 min by unilateral electrical stimulation of the PP (20 Hz, 10 s). During every other afterdischarge, the DG was illuminated for 5 or 30 s, first ipsilaterally and then bilaterally to the PP stimulation. The line length metric of the afterdischarges was compared between illumination conditions. ResultsIpsilateral stGtACR2 activation during afterdischarges decreased the local field potential line length only during illumination and specifically at the illuminated site but did not reduce afterdischarge duration. Bilateral illumination did not terminate the afterdischarges. ConclusionOptogenetic inhibition of excitatory neurons using the blue-light sensitive chloride channel stGtACR2 reduced the amplitude of electrically induced afterdischarges in the DG at the site of illumination, but this local inhibitory effect was insufficient to reduce the duration of the afterdischarge.

Vagus nerve stimulation (VNS) is an adjunctive therapy for drug-resistant epilepsy. Noninvasive evoked potential recordings in laryngeal muscles (LMEPs) innervated by vagal branches may provide a marker to assess effective vagal nerve fiber activation. We investigated VNS-induced LMEPs in patients with epilepsy in acute and chronic settings.A total of 17 of 25 patients underwent LMEP recordings at initiation of therapy (acute group); 15 of 25 patients after one year of VNS (chronic group); and 7 of 25 patients were tested at both time points (acute + chronic group). VNS-induced LMEPs were recorded following different pulse widths and output currents using six surface laryngeal EMG electrodes to calculate input/output curves and estimate LMEP latency, threshold current for minimal (IVNS-induced LMEPs were present in all patients. INoninvasive VNS-induced LMEP recording is feasible both at initiation of VNS therapy and after one year. Low output currents (0.25-1.00 mA) may be sufficient to activate vagal Aα-motor fibers. Maximal LMEP amplitudes seemed to decrease after chronic VNS therapy in patients.

Expression of inhibitory designer receptors exclusively activated by designer drugs (DREADDs) on excitatory hippocampal neurons in the hippocampus represents a potential new therapeutic strategy for drug-resistant epilepsy. To overcome the limitations of the commonly used DREADD agonist clozapine, we investigated the efficacy of the novel DREADD ligand JHU37160 in chemogenetic seizure suppression in the intrahippocampal kainic acid (IHKA) mouse model for temporal lobe epilepsy (TLE). In addition, seizure-suppressing effects of chemogenetics were compared to the commonly used anti-epileptic drug (AED), levetiracetam (LEV). Therefore, an adeno-associated viral vector was injected in the sclerotic hippocampus of IHKA mice to induce expression of a tagged inhibitory DREADD hM4Di or only a tag (control) specifically in excitatory neurons using the CamKIIα promoter. Subsequently, animals were treated with LEV (800 mg/kg), clozapine (0.1 mg/kg), and DREADD ligand JHU37160 (0.1 mg/kg) and the effect on spontaneous seizures was investigated. Clozapine and JHU37160-mediated chemogenetic treatment both suppressed seizures in DREADD-expressing IHKA mice. Clozapine treatment suppressed seizures up to 34 h after treatment, and JHU37160 effects lasted for 26 h after injection. Moreover, both compounds reduced the length of seizures that did occur after treatment up to 28 h and 18 h after clozapine and JHU37160, respectively. No seizure-suppressing effects were found in control animals using these ligands. Chemogenetic seizure treatment suppressed seizures during the first 30 min after injection, and seizures remained suppressed during 8 h following treatment. Chemogenetics thus outperformed effects of levetiracetam (p

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.

The measurement of birefringence variations related to nerve activity is a promising label-free technique for sensing compound neural action potentials (CNAPs). While widely applied in crustaceans, little is known about its efficiency on mammal peripheral nerves. In this work, birefringence recordings to detect CNAPs, and Stokes parameters measurements were performed in rat and lobster nerves. While single-trial detection of nerve activity in crustaceans was achieved successfully, no optical signal was detected in rats, even after extensive signal filtering and averaging. The Stokes parameters showed that a high degree of polarization of light is maintained in lobster sample, whereas an almost complete light depolarization occurs in rat nerve. Our results indicate that depolarization itself is not sufficient to explain the absence of birefringence signals in rats. We hypothesize that this absence comes from the myelin sheets, which constraint the birefringence changes to only take place at the nodes of Ranvier.

We report the design, synthesis, and validation of the novel compound photocaged N6-cyclopentyladenosine (cCPA) to achieve precisely localized and timed release of the parent adenosine A1 receptor agonist CPA using 405 nm light. Gi protein-coupled A1 receptors (A1Rs) modulate neurotransmission via pre- and post-synaptic routes. The dynamics of the CPA-mediated effect on neurotransmission, characterized by fast activation and slow recovery, make it possible to implement a closed-loop control paradigm. The strength of neurotransmission is monitored as the amplitude of stimulus-evoked local field potentials. It is used for feedback control of light to release CPA. This system makes it possible to regulate neurotransmission to a pre-defined level in acute hippocampal brain slices incubated with 3 µM cCPA. This novel approach of closed-loop photopharmacology holds therapeutic potential for fine-tuned control of neurotransmission in diseases associated with neuronal hyperexcitability.

Whiplash injuries typically occur from a motor vehicle collision and lead to chronic whiplash-associated disorders (CWAD) in 20% to 50% of cases. Changes in neurotransmission, metabolism, and networks seem to play a role in the pathogenic mechanism of CWAD.To further elucidate the functional brain alterations, a neurophysiological study was performed to investigate the somatosensory processing of CWAD patients by comparing the event-related potentials (ERPs) resulting from electrical nociceptive stimulation between patients suffering from CWAD and healthy controls (HC).Case-control study.University Hospital in Ghent.In this case-control study (CWAD patients/HC: 50/50), ankle and wrist electrical pain thresholds (EPT), and amplitude and latency of the event-related potentials (ERPs) resulting from 20 electrical stimuli were investigated. Correlations between the ERP characteristics, EPT, self-reported pain, disability, pain catastrophizing, and self-reported symptoms of central sensitization were investigated.Only the latency of the P3 component after left wrist stimulation (t = -2.283; P = 0.023) differed between both groups. In CWAD patients, the ankle EPT correlated with the amplitude of the corresponding P1 (rho s = 0.293; P = 0.044) and P3 (rho s = 0.306; P = 0.033), as well as with the amplitude of the P3 to left wrist stimulation (rho s = 0.343; P = 0.017). Self-reported symptoms of CS correlated with right wrist P3 amplitude (rho s = 0.308; P = 0.030) and latency (rho s = -0.341; P = 0.015), and the worst pain reported during the past week was correlated with left wrist P1 latency (rho s = 0.319; P = 0.029).Although the inclusion criteria stated that CWAD patients had to report a moderate-to-severe pain-related disability, 8 of the included CWAD patients (that scored above this threshold in the inclusion questionnaire), scored below the required cutoff at baseline.The CWAD patients did not show signs of hypersensitivity, but their ERP characteristics were related to the intensity of the applied stimulus, self-reported symptoms of CS, and the worst pain reported during the past week.

The pace of research and development in neuroscience, neurotechnology, and neurorehabilitation is rapidly accelerating, with the number of publications doubling every 4.2 years. Maintaining this progress requires technological standards and scientific reporting guidelines to provide frameworks for communication and interoperability. The present lack of such neurotechnology standards limits the transparency, repro-ducibility, and meta-analysis of this growing body of literature, posing an ongoing barrier to research, clinical, and commercial objectives. Continued neurotechnological innovation requires the development of some minimal standards to promote integration between this broad spectrum of technologies and therapies. To preserve design freedom and accelerate the translation of research into safe and effective technologies with maximal user benefit, such standards must be collaboratively co-developed by the full range of neuroscience and neurotechnology stakeholders. This paper summarizes the preliminary recommendations of IEEE P2794 Standards Working Group, developing a Reporting Standard for in-vivo Neural Interface Research (RSNIR).

Background: Recent experiments in rats have demonstrated significant effects of VNS on hippocampal excitability but were partially attributed to hypothermia, induced by the applied VNS parameters. Objective: To allow meaningful preclinical research on the mechanisms of VNS and translation of rodent results to clinical VNS trials, we aimed to identify non-hypothermia inducing VNS parameters that significantly affect hippocampal excitability. Methods: VNS was administered in cycles of 30 s including either 0.1, 0.16, 0.25, 0.5, 1.5, 3 or 7 s of VNS ON time (biphasic pulses, 250ms/phase, 1 mA, 30 Hz) and the effect of different VNS ON times on brain temperature was evaluated. VNS paradigms with and without hypothermia were compared for their effects on hippocampal neurophysiology in freely moving rats. Results: Using VNS parameters with an ON time/OFF time of up to 0.5 s/30 s did not cause hypothermia, while clear hypothermia was detected with ON times of 1.5, 3 and 7 s/30 s. Relative to SHAM VNS, the normothermic 0.5 s VNS condition significantly decreased hippocampal EEG power and changed dentate gyrus evoked potentials with an increased field excitatory postsynaptic potential slope and a decreased population spike amplitude. Conclusion: VNS can be administered in freely moving rats without causing hypothermia, while profoundly affecting hippocampal neurophysiology suggestive of reduced excitability of hippocampal neurons despite increased synaptic transmission efficiency. (C) 2020 The Authors. Published by Elsevier Inc.

OBJECTIVE: Deep brain stimulation (DBS) is an increasingly applied treatment for various neuropsychiatric disorders including drug-resistant epilepsy, and it may be optimized by rationalizing the stimulation protocol based on increased knowledge of its mechanism of action. We evaluated the effects of minutes to hours of hippocampal DBS on hippocampal evoked potentials (EPs) and local field potentials (LFPs) in freely moving male rats to further investigate some of the previously proposed mechanisms of action.METHODS: Hippocampal high-frequency (130 Hz) DBS was administered for 0, 1, or 6 min every 10 min for 160 min. Stimulation parameter settings were similar to those that had previously been shown to reduce seizures in epileptic rats. EPs and LFPs were recorded in the stimulation-free intervals. We investigated both the immediate temporary effects of 1 or 6 min of DBS and the effects of 160 min of intermittent DBS. Input specificity was investigated by using two different stimulation electrodes.RESULTS: Relatively low DBS intensities corresponding to only 1.8% of the intensity evoking a maximum EP were required to prevent unintended seizure occurrence in healthy rats. Both 1 and 6 min of DBS caused input-specific short-lasting (P = .005). We observed longer-lasting, input-specific EP reductions during the 160 min intermittent DBS, with statistically significant reductions (3%-4%) of the fEPSP slope (P = .009-.018). The LFP spectrogram remained unaltered.SIGNIFICANCE: Deep brain stimulation induced both acute temporary effects compatible with axonal block and/or synaptic depression, and longer-lasting potentially cumulative EP reductions, suggesting the involvement of homeostatic plasticity or long-term depression. This dual time course may parallel the different temporal patterns of improvement observed in clinical trials. The longer-lasting reductions provide a potential neurophysiological basis for the use of intermittent DBS-as typically used in epilepsy patients-as an alternative to continuous DBS.

Objectives: As a potential treatment for epilepsy, transcutaneous auricular vagus nerve stimulation (taVNS) has yielded inconsistent results. Combining transcranial magnetic stimulation with electromyography (TMS-EMG) and electroencephalography (TMS-EEG) can be used to investigate the effect of interventions on cortical excitability by evaluating changes in motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs). The goal of this study is to objectively evaluate the effect of taVNS on cortical excitability with TMS-EMG and TMS-EEG. These findings are expected to provide insight in the mechanism of action and help identify more optimal stimulation paradigms. Materials and Methods: In this prospective single-blind cross-over study, 15 healthy male subjects underwent active and sham taVNS for 60 min, using a maximum tolerated stimulation current. Single and paired pulse TMS was delivered over the right-sided motor hotspot to evaluate MEPs and TEPs before and after the intervention. MEP statistical analysis was conducted with a two-way repeated measures ANOVA. TEPs were analyzed with a cluster-based permutation analysis. Linear regression analysis was implemented to investigate an association with stimulation current. Results: MEP and TEP measurements were not affected by taVNS in this study. An association was found between taVNS stimulation current and MEP outcome measures indicating a decrease in cortical excitability in participants who tolerated higher taVNS currents. A subanalysis of participants (n = 8) who tolerated a taVNS current ≥2.5 mA showed a significant increase in the resting motor threshold, decrease in MEP amplitude and modulation of the P60 and P180 TEP components. Conclusions: taVNS did not affect cortical excitability measurements in the overall population in this study. However, taVNS has the potential to modulate specific markers of cortical excitability in participants who tolerate higher stimulation levels. These findings indicate the need for adequate stimulation protocols based on the recording of objective outcome parameters.

AimGtACR2, a light-activated chloride channel, is an attractive tool for neural inhibition as it can shunt membrane depolarizations. In this study, we assessed the effect of activating GtACR2 on in vivo hippocampal CA1 activity evoked by Schaffer collateral (SC) stimulation.MethodsAdult male Wistar rats were unilaterally injected with 0.5 μL of adeno associated viral vector for induction of GtACR2-mCherry (n = 10, GtACR2 group) or mCherry (n = 4, Sham group) expression in CA1 pyramidal neurons of the hippocampus. Three weeks later, evoked potentials (EPs) were recorded from the CA1 subfield placing an optrode (bipolar recording electrode attached to an optic fiber) at the injection site and a stimulation electrode targeting SCs. Effects of illumination parameters required to activate GtACR2 such as light power densities (LPDs), illumination delays, and light-pulse durations were tested on CA1 EP parameters [population spike (PS) amplitude and field excitatory postsynaptic potential (fEPSP) slope].ResultsIn the GtACR2 group, delivery of a 10 ms light-pulse induced a negative deflection in the local field potential which increased with increasing LPD. When combined with electrical stimulation of the SCs, light-induced activation of GtACR2 had potent inhibitory effects on CA1 EPs. An LPD of 160 mW/mm2 was sufficient to obtain maximal inhibition CA1 EPs. To quantify the duration of the inhibitory effect, a 10 ms light-pulse of 160 mW/mm2 was delivered at increasing delays before the CA1 EPs. Inhibition of EPs was found to last up to 9 ms after the cessation of the light-pulse. Increasing light-pulse durations beyond 10 ms did not result in larger inhibitory effects.ConclusionPrecisely timed activation of GtACR2 potently blocks evoked activity of CA1 neurons. The strength of inhibition depends on LPD, lasts up to 9 ms after a light-pulse of 10 ms, and is independent of the duration of the light-pulse given.