Exploration of Theta Burst-Induced Modulation of Transcranial Magnetic Stimulation-Evoked Potentials Over the Motor Cortex.

OBJECTIVES: This study investigates the way theta burst stimulation (TBS) applied to the motor cortex (M1) affects TMS-evoked potentials (TEPs). There have been few direct comparisons of continuous TBS (cTBS) and intermittent TBS (iTBS), and there is a lack of consensus from existing literature on the induced effects. We performed an exploratory trial to assess the effect of M1-cTBS and M1-iTBS on TEP components. MATERIALS AND METHODS: In a cross-over design, 15 participants each completed three experimental sessions with ≥one week in between sessions. The effect of a single TBS train administered over M1 was investigated using TEPs recorded at the same location, 20 to 30 minutes before and in the first 10 minutes after the intervention. In each session, a different type of TBS (cTBS, iTBS, or active control cTBS) was administered in a single-blinded randomized order. For six different TEP components (N15, P30, N45, P60, N100, and P180), amplitude was compared before and after the intervention using cluster-based permutation (CBP) analysis. RESULTS: We were unable to identify a significant modulation of any of the six predefined M1 TEP components after a single train of TBS. When waiving statistical correction for multiple testing in view of the exploratory nature of the study, the CBP analysis supports a reduction of the P180 amplitude after iTBS (p = 0.015), whereas no effect was observed after cTBS or in the active control condition. The reduction occurred in ten of 15 subjects, showing intersubject variability. CONCLUSIONS: The observed decrease in the P180 amplitude after iTBS may suggest a neuromodulatory effect of iTBS. Despite methodologic issues related to our study and the potential sensory contamination within this latency range of the TEP, we believe that our finding deserves further investigation in hypothesis-driven trials of adequate power and proper design, focusing on disentanglement between TEPs and peripherally evoked potentials, in addition to indicating reproducibility across sessions and subjects. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT05206162.

Increased Dentate Gyrus Excitability in the Intrahippocampal Kainic Acid Mouse Model for Temporal Lobe Epilepsy.

The intrahippocampal kainic acid (IHKA) mouse model is an extensively used in vivo model to investigate the pathophysiology of mesial temporal lobe epilepsy (mTLE) and to develop novel therapies for drug-resistant epilepsy. It is characterized by profound hippocampal sclerosis and spontaneously occurring seizures with a major role for the injected damaged hippocampus, but little is known about the excitability of specific subregions. The purpose of this study was to electrophysiologically characterize the excitability of hippocampal subregions in the chronic phase of the induced epilepsy in the IHKA mouse model. We recorded field postsynaptic potentials (fPSPs) after electrical stimulation in the CA1 region and in the dentate gyrus (DG) of hippocampal slices of IHKA and healthy mice using a multielectrode array (MEA). In the DG, a significantly steeper fPSP slope was found, reflecting higher synaptic strength. Population spikes were more prevalent with a larger spatial distribution in the IHKA group, reflecting a higher degree of granule cell output. Only minor differences were found in the CA1 region. These results point to increased neuronal excitability in the DG but not in the CA1 region of the hippocampus of IHKA mice. This method, in which the excitability of hippocampal slices from IHKA mice is investigated using a MEA, can now be further explored as a potential new model to screen for new interventions that can restore DG function and potentially lead to novel therapies for mTLE.

Investigating the Effect of Transcutaneous Auricular Vagus Nerve Stimulation on Cortical Excitability in Healthy Males.

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.

Laryngeal Muscle-Evoked Potential Recording as an Indicator of Vagal Nerve Fiber Activation.

BACKGROUND: 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. MATERIALS AND METHODS: 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 (Ithreshold), half-maximal (I50), and 95% of maximal (I95) response induction and amplitude of maximal response (Vmax). These were compared with the acute + chronic group and between responders and nonresponders in the acute and chronic group. RESULTS: VNS-induced LMEPs were present in all patients. Ithreshold and I95 values ranged from 0.25 to 1.00 mA and from 0.42 to 1.77 mA, respectively. Estimated mean LMEP latencies were 10 ± 0.1 milliseconds. No significant differences between responders and nonresponders were observed. In the acute + chronic group, Ithreshold values remained stable over time. However, at the individual level in this group, Vmax was lower in all patients after one year compared with baseline. CONCLUSIONS: Noninvasive 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.

Ex Vivo Feedback Control of Neurotransmission Using a Photocaged Adenosine A1 Receptor Agonist.

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.

Long-term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy.

OBJECTIVE: One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons. METHODS: Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction. RESULTS: In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection. SIGNIFICANCE: This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.

Deep brain stimulation reduces evoked potentials with a dual time course in freely moving rats: Potential neurophysiological basis for intermittent as an alternative to continuous stimulation.

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 (<60 s) reductions (5%-7%) of the field excitatory postsynaptic potential (fEPSP) slope (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.

Correction to: Safety of long-term electrical peripheral nerve stimulation: review of the state of the art.

An amendment to this paper has been published and can be accessed via the original article.

Long-term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy.

OBJECTIVE: More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. METHODS: Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. RESULTS: Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. SIGNIFICANCE: This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.

Safety of long-term electrical peripheral nerve stimulation: review of the state of the art.

BACKGROUND: Electrical stimulation of peripheral nerves is used in a variety of applications such as restoring motor function in paralyzed limbs, and more recently, as means to provide intuitive sensory feedback in limb prostheses. However, literature on the safety requirements for stimulation is scarce, particularly for chronic applications. Some aspects of nerve interfacing such as the effect of stimulation parameters on electrochemical processes and charge limitations have been reviewed, but often only for applications in the central nervous system. This review focuses on the safety of electrical stimulation of peripheral nerve in humans. METHODS: We analyzed early animal studies evaluating damage thresholds, as well as more recent investigations in humans. Safety requirements were divided into two main categories: passive and active safety. We made the distinction between short-term (< 30 days) and chronic (> 30 days) applications, as well as between electrode preservation (biostability) and body tissue healthy survival (harmlessness). In addition, transferability of experimental results between different tissues and species was considered. RESULTS: At present, extraneural electrodes have shown superior long-term stability in comparison to intraneural electrodes. Safety limitations on pulse amplitude (and consequently, charge injection) are dependent on geometrical factors such as electrode placement, size, and proximity to the stimulated fiber. In contrast, other parameters such as stimulation frequency and percentage of effective stimulation time are more generally applicable. Currently, chronic stimulation at frequencies below 30 Hz and percentages of effective stimulation time below 50% is considered safe, but more precise data drawn from large databases are necessary. Unfortunately, stimulation protocols are not systematically documented in the literature, which limits the feasibility of meta-analysis and impedes the generalization of conclusions. We therefore propose a standardized list of parameters necessary to define electrical stimulation and allow future studies to contribute to meta-analyses. CONCLUSION: The safety of chronic continuous peripheral nerve stimulation at frequencies higher than 30 Hz has yet to be documented. Precise parameter values leading to stimulation-induced depression of neuronal excitability (SIDNE) and neuronal damage, as well as the transition between the two, are still lacking. At present, neural damage mechanisms through electrical stimulation remain obscure.

Disruption, but not overexpression of urate oxidase alters susceptibility to pentylenetetrazole- and pilocarpine-induced seizures in mice.

There is a continuous drive to find new, improved therapies that have a different mechanism of action in order to help diminish the sizable percentage of persons with pharmacoresistant epilepsy. Uric acid is increasingly recognized as contributing to the pathophysiology of multiple disorders, and there are indications that uric acid might play a role in epileptic mechanisms. Nevertheless, studies that directly investigate its involvement are lacking. In this study we assessed the susceptibility to pentylenetetrazole- and pilocarpine-induced seizures in mice with genetically altered uric acid levels by targeting urate oxidase, which is the enzyme responsible for uric acid breakdown. We found that although disruption of urate oxidase resulted in a decreased susceptibility to all behavioral end points in both seizure models, overexpression did not result in any alterations when compared to their wild-type littermates. Our results suggest that a chronic increase in uric acid levels may result in decreased brain excitability.

A model of space-fractional-order diffusion in the glial scar.

Implantation of neuroprosthetic electrodes induces a stereotypical state of neuroinflammation, which is thought to be detrimental for the neurons surrounding the electrode. Mechanisms of this type of neuroinflammation are still poorly understood. Recent experimental and theoretical results point to a possible role of the diffusing species in this process. The paper considers a model of anomalous diffusion occurring in the glial scar around a chronic implant in two simple geometries - a separable rectilinear electrode and a cylindrical electrode, which are solvable exactly. We describe a hypothetical extended source of diffusing species and study its concentration profile in steady-state conditions. Diffusion transport is assumed to obey a fractional-order Fick law, derivable from physically realistic assumptions using a fractional calculus approach. Presented fractional-order distribution morphs into integer-order diffusion in the case of integral fractional exponents. The model demonstrates that accumulation of diffusing species can occur and the scar properties (i.e. tortuosity, fractional order, scar thickness) and boundary conditions can influence such accumulation. The observed shape of the concentration profile corresponds qualitatively with GFAP profiles reported in the literature. The main difference with respect to the previous studies is the explicit incorporation of the apparatus of fractional calculus without assumption of an ad hoc tortuosity parameter. The approach can be adapted to other studies of diffusion in biological tissues, for example of biomolecules or small drug molecules.

Electroencephalogram synchronization measure as a predictive biomarker of Vagus nerve stimulation response in refractory epilepsy: A retrospective study.

There are currently no established biomarkers for predicting the therapeutic effectiveness of Vagus Nerve Stimulation (VNS). Given that neural desynchronization is a pivotal mechanism underlying VNS action, EEG synchronization measures could potentially serve as predictive biomarkers of VNS response. Notably, an increased brain synchronization in delta band has been observed during sleep-potentially due to an activation of thalamocortical circuitry, and interictal epileptiform discharges are more frequently observed during sleep. Therefore, investigation of EEG synchronization metrics during sleep could provide a valuable insight into the excitatory-inhibitory balance in a pro-epileptogenic state, that could be pathological in patients exhibiting a poor response to VNS. A 19-channel-standard EEG system was used to collect data from 38 individuals with Drug-Resistant Epilepsy (DRE) who were candidates for VNS implantation. An EEG synchronization metric-the Weighted Phase Lag Index (wPLI)-was extracted before VNS implantation and compared between sleep and wakefulness, and between responders (R) and non-responders (NR). In the delta band, a higher wPLI was found during wakefulness compared to sleep in NR only. However, in this band, no synchronization difference in any state was found between R and NR. During sleep and within the alpha band, a negative correlation was found between wPLI and the percentage of seizure reduction after VNS implantation. Overall, our results suggest that patients exhibiting a poor VNS efficacy may present a more pathological thalamocortical circuitry before VNS implantation. EEG synchronization measures could provide interesting insights into the prerequisites for responding to VNS, in order to avoid unnecessary implantations in patients showing a poor therapeutic efficacy.

An optoelectronic implantable neurostimulation platform allowing full MRI safety and optical sensing and communication.

A novel programmable implantable neurostimulation platform based on photonic power transfer has been developed for various clinical applications with the main focus of being safe to use with MRI scanners. The wires usually conveying electrical current from the neurostimulator to the electrodes are replaced by optical fibers. Photovoltaic cells at the tip of the fibers convert laser light to biphasic electrical impulses together with feedback signals with 54% efficiency. Furthermore, a biocompatible, implantable and ultra-flexible optical lead was developed including custom optical fibers. The neurostimulator platform incorporates advanced signal processing and optical physiological sensing capabilities thanks to a hermetically sealed transparent nonmetallic casing. Skin transparency also allowed the development of a high-speed optical transcutaneous communication channel. This implantable neurostimulation platform was first adapted to a vagus nerve stimulator for the treatment of epilepsy. This neurostimulator has been designed to fulfill the requirements of a class III long-term implantable medical device. It has been proven compliant with standard ISO/TS10974 for 1.5 T and 3 T MRI scanners. The device poses no related threat and patients can safely undergo MRI without specific or additional precautions. Especially, the RF induced heating near the implant remains below 2 °C whatever the MRI settings used. The main features of this unique advanced neurostimulator and its architecture are presented. Its functional performance is evaluated, and results are described with a focus on optoelectronics aspects and MRI safety.

Effect on signal-to-noise ratio of splitting the continuous contacts of cuff electrodes into smaller recording areas.

BACKGROUND: Cuff electrodes have been widely used chronically in different clinical applications. This neural interface has been dominantly used for nerve stimulation while interfering noise is the major issue when employed for recording purposes. Advancements have been made in rejecting extra-neural interference by using continuous ring contacts in tripolar topologies. Ring contacts provide an average of the neural activity, and thus reduce the information retrieved. Splitting these contacts into smaller recording areas could potentially increase the information content. In this study, we investigate the impact of such discretization on the Signal-to-Noise Ratio (SNR). The effect of contacts positioning and an additional short circuited pair of electrodes were also addressed. METHODS: Different recording configurations using ring, dot, and a mixed of both contacts were studied in vitro in a frog model. An interfering signal was induced in the medium to simulate myoelectric noise. The experimental setup was design in such a way that the only difference between recordings was the configuration used. The inter-session experimental differences were taken care of by a common configuration that allowed normalization between electrode designs. RESULTS: It was found that splitting all contacts into small recording areas had negative effects on noise rejection. However, if this is only applied to the central contact creating a mixed tripole configuration, a considerable and statistically significant improvement was observed. Moreover, the signal to noise ratio was equal or larger than what can be achieved with the best known configuration, namely the short circuited tripole. This suggests that for recording purposes, any tripole topology would benefit from splitting the central contact into one or more discrete contacts. CONCLUSIONS: Our results showed that a mixed tripole configuration performs better than the configuration including only ring contacts. Therefore, splitting the central ring contact of a cuff electrode into a number of dot contacts not only provides additional information but also an improved SNR. In addition, the effect of an additional pair of short circuited electrodes and the "end effect" observed with the presented method are in line with previous findings by other authors.

Vagus nerve stimulation-induced laryngeal motor evoked potentials for response prediction and intensity titration in drug-resistant epilepsy.

OBJECTIVE: 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.

Functional brain connectivity indexes derived from low-density EEG of pre-implanted patients as VNS outcome predictors.

Objective. In 1/3 of patients, anti-seizure medications may be insufficient, and resective surgery may be offered whenever the seizure onset is localized and situated in a non-eloquent brain region. When surgery is not feasible or fails, vagus nerve stimulation (VNS) therapy can be used as an add-on treatment to reduce seizure frequency and/or severity. However, screening tools or methods for predicting patient response to VNS and avoiding unnecessary implantation are unavailable, and confident biomarkers of clinical efficacy are unclear.Approach. To predict the response of patients to VNS, functional brain connectivity measures in combination with graph measures have been primarily used with respect to imaging techniques such as functional magnetic resonance imaging, but connectivity graph-based analysis based on electrophysiological signals such as electroencephalogram, have been barely explored. Although the study of the influence of VNS on functional connectivity is not new, this work is distinguished by using preimplantation low-density EEG data to analyze discriminative measures between responders and non-responder patients using functional connectivity and graph theory metrics.Main results. By calculating five functional brain connectivity indexes per frequency band upon partial directed coherence and direct transform function connectivity matrices in a population of 37 refractory epilepsy patients, we found significant differences (p< 0.05) between the global efficiency, average clustering coefficient, and modularity of responders and non-responders using the Mann-Whitney U test with Benjamini-Hochberg correction procedure and use of a false discovery rate of 5%.Significance. Our results indicate that these measures may potentially be used as biomarkers to predict responsiveness to VNS therapy.

In vivo inhibition of epileptiform afterdischarges in rat hippocampus by light-activated chloride channel, stGtACR2.

AIMS: The 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. METHODS: Rats were bilaterally injected with 0.9 µl of AAV2/7-CaMKIIα-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. RESULTS: Ipsilateral 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. CONCLUSION: Optogenetic 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.

Heat accumulation during infrared stimulation impacts the response of ex vivo rat sciatic nerve.

Infrared neural stimulation (INS) is a neuromodulation technique that involves short optical pulses delivered to the neural tissue, resulting in the initiation of action potentials. In this work, we studied the compound neural action potentials (CNAP) generated by INS in five ex vivo sciatic nerves. A 1470 nm laser emitting a sequence of 0.4 ms light pulses with a peak power of 10 W was used. A single 4 mJ stimulus is not capable of eliciting a nerve response. However, repetition of the optical stimuli resulted in the induction of CNAPs. Heat accumulation induced by repetition rates as high as 10 Hz may be involved in the increase in CNAP amplitude. This sensitization effect may help to reduce the pulse energy required to evoke CNAP. In addition, these results highlight the importance of investigating the role of the slow nerve temperature dynamics in INS.

On the viability of implantable electrodes for the natural control of artificial limbs: review and discussion.

The control of robotic prostheses based on pattern recognition algorithms is a widely studied subject that has shown promising results in acute experiments. The long-term implementation of this technology, however, has not yet been achieved due to practical issues that can be mainly attributed to the use of surface electrodes and their highly environmental dependency. This paper describes several implantable electrodes and discusses them as a solution for the natural control of artificial limbs. In this context "natural" is defined as producing control over limb movement analogous to that of an intact physiological system. This includes coordinated and simultaneous movements of different degrees of freedom. It also implies that the input signals must come from nerves or muscles that were originally meant to produce the intended movement and that feedback is perceived as originating in the missing limb without requiring burdensome levels of concentration. After scrutinizing different electrode designs and their clinical implementation, we concluded that the epimysial and cuff electrodes are currently promising candidates to achieving a long-term stable and natural control of robotic prosthetics, provided that communication from the electrodes to the outside of the body is guaranteed.