Imagined speech event detection from electrocorticography and its transfer between speech modes and subjects.

Speech brain-computer interfaces aim to support communication-impaired patients by translating neural signals into speech. While impressive progress was achieved in decoding performed, perceived and attempted speech, imagined speech remains elusive, mainly due to the absence of behavioral output. Nevertheless, imagined speech is advantageous since it does not depend on any articulator movements that might become impaired or even lost throughout the stages of a neurodegenerative disease. In this study, we analyzed electrocortigraphy data recorded from 16 participants in response to 3 speech modes: performed, perceived (listening), and imagined speech. We used a linear model to detect speech events and examined the contributions of each frequency band, from delta to high gamma, given the speech mode and electrode location. For imagined speech detection, we observed a strong contribution of gamma bands in the motor cortex, whereas lower frequencies were more prominent in the temporal lobe, in particular of the left hemisphere. Based on the similarities in frequency patterns, we were able to transfer models between speech modes and participants with similar electrode locations.

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.

Investigating the Working Mechanism of Transcranial Direct Current Stimulation.

BACKGROUND: Transcranial direct current stimulation (tDCS) is used to modulate neuronal activity, but the exact mechanism of action (MOA) is unclear. This study investigates tDCS-induced modulation of the corticospinal excitability and the underlying MOA. By anesthetizing the scalp before applying tDCS and by stimulating the cheeks, we investigated whether stimulation of peripheral and/or cranial nerves contributes to the effects of tDCS on corticospinal excitability. MATERIALS AND METHODS: In a randomized cross-over study, four experimental conditions with anodal direct current stimulation were compared in 19 healthy volunteers: 1) tDCS over the motor cortex (tDCS-MI), 2) tDCS over the motor cortex with a locally applied topical anesthetic (TA) on the scalp (tDCS-MI + TA), 3) DCS over the cheek region (DCS-C), and 4) sham tDCS over the motor cortex(sham). tDCS was applied for 20 minutes at 1 mA. Motor evoked potentials (MEPs) were measured before tDCS and immediately, 15, 30, 45, and 60 minutes after tDCS. A questionnaire was used to assess the tolerability of tDCS. RESULTS: A significant MEP amplitude increase compared with baseline was found 30 minutes after tDCS-MI, an effect still observed 60 minutes later; no time∗condition interaction effect was detected. In the other three conditions (tDCS-MI + TA, DCS-C, sham), no significant MEP modulation was found. The questionnaire indicated that side effects are significantly lower when the local anesthetic was applied before stimulation than in the other three conditions. CONCLUSIONS: The significant MEP amplitude increase observed from 30 minutes on after tDCS-MI supports the modulatory effect of tDCS on corticospinal neurotransmission. This effect lasted one hour after stimulation. The absence of a significant modulation when a local anesthetic was applied suggests that effects of tDCS are not solely established through direct cortical stimulation but that stimulation of peripheral and/or cranial nerves also might contribute to tDCS-induced modulation.

Vagus nerve stimulation enhances remyelination and decreases innate neuroinflammation in lysolecithin-induced demyelination.

BACKGROUND: Current treatments for Multiple Sclerosis (MS) poorly address chronic innate neuroinflammation nor do they offer effective remyelination. The vagus nerve has a strong regulatory role in inflammation and Vagus Nerve Stimulation (VNS) has potential to affect both neuroinflammation and remyelination in MS. OBJECTIVE: This study investigated the effects of VNS on demyelination and innate neuroinflammation in a validated MS rodent model. METHODS: Lysolecithin (LPC) was injected in the corpus callosum (CC) of 46 Lewis rats, inducing a demyelinated lesion. 33/46 rats received continuously-cycled VNS (cVNS) or one-minute per day VNS (1minVNS) or sham VNS from 2 days before LPC-injection until perfusion at 3 days post-injection (dpi) (corresponding with a demyelinated lesion with peak inflammation). 13/46 rats received cVNS or sham from 2 days before LPC-injection until perfusion at 11 dpi (corresponding with a partial remyelinated lesion). Immunohistochemistry and proteomics analyses were performed to investigate the extend of demyelination and inflammation. RESULTS: Immunohistochemistry showed that cVNS significantly reduced microglial and astrocytic activation in the lesion and lesion border, and significantly reduced the Olig2+ cell count at 3 dpi. Furthermore, cVNS significantly improved remyelination with 57.4 % versus sham at 11 dpi. Proteomic gene set enrichment analyses showed increased activation of (glutamatergic) synapse pathways in cVNS versus sham, most pronounced at 3 dpi. CONCLUSION: cVNS improved remyelination of an LPC-induced lesion. Possible mechanisms might include modulation of microglia and astrocyte activity, increased (glutamatergic) synapses and enhanced oligodendrocyte clearance after initial injury.

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.

Hippocampal seizures differentially modulate locus coeruleus activity and result in consistent time-locked release of noradrenaline in rat hippocampus.

The locus coeruleus (LC) is a small brainstem nucleus and is the sole source of noradrenaline in the neocortex, hippocampus and cerebellum. Noradrenaline is a powerful neuromodulator involved in the regulation of excitability and plasticity of large-scale brain networks. In this study, we performed a detailed assessment of the activity of locus coeruleus neurons and changes in noradrenergic transmission during acute hippocampal seizures evoked with perforant path stimulation, using state-of-the-art methodology. Action potentials of LC neurons, of which some were identified by means of optogenetics, were recorded in anesthetized rats using a multichannel high-density electrophysiology probe. The seizure-induced change in firing rate differed between LC neurons: 55% of neurons decreased in firing rate during seizures, while 28% increased their firing rate. Topographic analysis of multi-unit activity over the electrophysiology probe showed a topographic clustering of neurons that were inhibited or excited during seizures. Changes in hippocampal noradrenaline transmission during seizures were assessed using a fluorescent biosensor for noradrenaline, GRABNE2m, in combination with fiber photometry, in both anesthetized and awake rats. Although our neuronal recordings indicated both inhibition and excitation of LC neurons during seizures, a consistent release of noradrenaline was observed. Concentrations of noradrenaline increased at seizure onset and decreased during or shortly after the seizure. In conclusion, this study showed consistent but heterogeneous modulation of LC neurons and a consistent time-locked release of hippocampal noradrenaline during acute hippocampal seizures.

Cognitive tasks propagate the neural entrainment in response to a visual 40 Hz stimulation in humans.

Introduction: Alzheimer's disease is one of the great challenges in the coming decades, and despite great efforts, a widely effective disease-modifying therapy in humans remains elusive. One particular promising non-pharmacological therapy that has received increased attention in recent years is based on the Gamma ENtrainment Using Sensory stimulation (GENUS), a high-frequency neural response elicited by a visual and/or auditory stimulus at 40 Hz. While this has shown to be effective in animal models, studies on human participants have reported varying success. The current work hypothesizes that the varying success in humans is due to differences in cognitive workload during the GENUS sessions. Methods: We recruited a cohort of 15 participants who underwent a scalp-EEG recording as well as one epilepsy patient who was implanted with 50 subdural surface electrodes over temporo-occipital and temporo-basal cortex and 14 depth contacts that targeted the hippocampus and insula. All participants completed several GENUS sessions, in each of which a different cognitive task was performed. Results: We found that the inclusion of a cognitive task during the GENUS session not only has a positive effect on the strength and extent of the gamma entrainment, but also promotes the propagation of gamma entrainment to additional neural areas including deep ones such as hippocampus which were not recruited when no cognitive task was required from the participants. The latter is of particular interest given that the hippocampal complex is considered to be one of the primary targets for AD therapies. Discussion: This work introduces a possible improvement strategy for GENUS therapy that might contribute to increasing the efficacy of the therapy or shortening the time needed for the positive outcome.

Continuous theta burst stimulation for drug-resistant epilepsy.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) may have anti-epileptic effects, especially in patients with neocortical lesions. Initial clinical trials demonstrated that the duration of the seizure reducing effect is relatively short-lived. In the context of a chronic condition like epilepsy, theta burst stimulation (TBS) may represent a potential solution in optimizing treatment practicality and durability as it was demonstrated to be associated with longer-lasting after-effects. TBS has been studied extensively in diverse neuropsychiatric conditions, but a therapeutic TBS protocol has not previously been applied in epilepsy patients. Materials and methods: We performed a prospective open-label pilot study of 4-day accelerated continuous TBS (cTBS) treatment in patients with neocortical drug-resistant epilepsy (DRE). A treatment session consisted of 5 cTBS trains, each comprising 600 pulses presented in 50 Hz triplet bursts every 200 ms, delivered at 10-min intertrain-intervals, targeted over the epileptic focus (EF) using a neuronavigation-guided figure-of-8 coil. Safety and feasibility, and seizure frequency were assessed as primary and secondary endpoints, respectively, over a 4-week baseline period, a 1-week treatment period and a 7-week follow-up period, using adverse event logging, electro-encephalography, cognitive, and psychological questionnaires and a seizure diary kept by the patients and/or caregivers. Results: Seven subjects (4M:3F; median age 48, interquartile ranges 25) underwent the treatment protocol. Adverse events were reported in all subjects but were mild and transient. No clinical or electrographic seizures were evoked during or immediately following stimulation. No deterioration was found in cognition nor in psycho-emotional well-being following treatment. Treatment burden was acceptable, but seems to depend on clinical effect, duration of ongoing effect and stimulation site. Median weekly seizure frequency and ratio of seizure-free weeks did not change significantly in this small patient cohort. Conclusion: We report the results of the first ever trial of cTBS as a treatment for neocortical DRE. A 4-day accelerated cTBS protocol over the EF appears safe and feasible. Although the design and sample size of this open-label pilot study is unfit to reliably identify a therapeutic effect, results encourage further exploration of cTBS as an anti-epileptic treatment and potential optimization compared to conventional rTMS in a dedicated randomized controlled trial. (clinicaltrials.gov: NCT02635633).

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.

Recent Advances in the Use of Focused Ultrasound as a Treatment for Epilepsy.

Epilepsy affects about 1% of the population. Approximately one third of patients with epilepsy are drug-resistant (DRE). Resective surgery is an effective treatment for DRE, yet invasive, and not all DRE patients are suitable resective surgery candidates. Focused ultrasound, a novel non-invasive neurointerventional method is currently under investigation as a treatment alternative for DRE. By emitting one or more ultrasound waves, FUS can target structures in the brain at millimeter resolution. High intensity focused ultrasound (HIFU) leads to ablation of tissue and could therefore serve as a non-invasive alternative for resective surgery. It is currently under investigation in clinical trials following the approval of HIFU for essential tremor and Parkinson's disease. Low intensity focused ultrasound (LIFU) can modulate neuronal activity and could be used to lower cortical neuronal hyper-excitability in epilepsy patients in a non-invasive manner. The seizure-suppressive effect of LIFU has been studied in several preclinical trials, showing promising results. Further investigations are required to demonstrate translation of preclinical results to human subjects.

Personalized tDCS for Focal Epilepsy-A Narrative Review: A Data-Driven Workflow Based on Imaging and EEG Data.

Conventional transcranial electric stimulation(tES) using standard anatomical positions for the electrodes and standard stimulation currents is frequently not sufficiently selective in targeting and reaching specific brain locations, leading to suboptimal application of electric fields. Recent advancements in in vivo electric field characterization may enable clinical researchers to derive better relationships between the electric field strength and the clinical results. Subject-specific electric field simulations could lead to improved electrode placement and more efficient treatments. Through this narrative review, we present a processing workflow to personalize tES for focal epilepsy, for which there is a clear cortical target to stimulate. The workflow utilizes clinical imaging and electroencephalography data and enables us to relate the simulated fields to clinical outcomes. We review and analyze the relevant literature for the processing steps in the workflow, which are the following: tissue segmentation, source localization, and stimulation optimization. In addition, we identify shortcomings and ongoing trends with regard to, for example, segmentation quality and tissue conductivity measurements. The presented processing steps result in personalized tES based on metrics like focality and field strength, which allow for correlation with clinical outcomes.

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.

The potential of invasive and non-invasive vagus nerve stimulation to improve verbal memory performance in epilepsy patients.

It has been demonstrated that acute vagus nerve stimulation (VNS) improves word recognition memory in epilepsy patients. Transcutaneous auricular vagus nerve stimulation (taVNS) has gained interest as a non-invasive alternative to improve cognition. In this prospective randomized cross-over study, we investigated the effect of both invasive VNS and taVNS on verbal memory performance in 15 patients with drug-resistant epilepsy. All patients conducted a word recognition memory paradigm in 3 conditions: VNS ON, VNS OFF and taVNS (3-period 3-treatment cross-over study design). For each condition, patients memorized 21 highlighted words from text paragraphs. Afterwards, the intervention was delivered for 30 s. Immediate recall and delayed recognition scores were obtained for each condition. This memory paradigm was repeated after 6 weeks of VNS therapy in 2 conditions: VNS ON and VNS OFF (2-period 2-treatment cross-over study design). Acute VNS and taVNS did not improve verbal memory performance. Immediate recall and delayed recognition scores were significantly improved after 6 weeks of VNS treatment irrespective of the acute intervention. We can conclude that the previously described positive effects of invasive VNS on verbal memory performance could not be replicated with invasive VNS and taVNS. An improved verbal memory performance was seen after 6 weeks of VNS treatment, suggesting that longer and more repetitive stimulation of the vagal pathway is required to modulate verbal memory performance.Clinical trial registration number: NCT05031208.

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.

Transcutaneous auricular vagus nerve stimulation cannot modulate the P3b event-related potential in healthy volunteers.

OBJECTIVE: The release of cortical norepinephrine is one of the possible mechanisms of action of vagus nerve stimulation (VNS), a neuromodulatory treatment currently under investigation for cognitive impairment. Transcutaneous auricular VNS (taVNS) may be able to activate vagal nerve branches ending in the brainstem's locus coeruleus (LC) non-invasively. The aim was to investigate if acute taVNS can modulate the P3b, a cognitive event-related potential (ERP) reflecting noradrenergic brain activation under control of the LC. METHODS: Thirty-nine healthy volunteers performed an auditory oddball task during no stimulation, sham stimulation and taVNS in a randomized order. P3b amplitude, latency and behavioral outcome parameters were compared between conditions using linear mixed models. RESULTS: P3b amplitude and latency during taVNS did not differ significantly from sham or control. Reaction time shortened and P3b latency prolonged with repetition of the oddball task. CONCLUSIONS: We were unable to modulate cognitive ERPs by means of acute taVNS in a large group of healthy volunteers. SIGNIFICANCE: Targeting vagal nerve fibres via a transcutaneous approach did not alter the P3b in healthy participants. The stimulation parameters used and transient delivery of taVNS might be insufficient to adequately modulate the LC. Also, a disbalanced locus coeruleus - norepinephrine system in patients may be more prone for improvement.

Chemogenetic Seizure Control with Clozapine and the Novel Ligand JHU37160 Outperforms the Effects of Levetiracetam in the Intrahippocampal Kainic Acid Mouse Model.

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 < 0.001), which suppressed seizure frequency with a maximum of 55 ± 9% for up to 1.5 h (p < 0.05). Only chemogenetic and not levetiracetam treatment affected the length of seizures after treatment (p < 0.001). These results show that the chemogenetic therapeutic strategy with either clozapine or JHU37160 effectively suppresses spontaneous seizures in the IHKA mouse model, confirming JHU37160 as an effective DREADD ligand. Moreover, chemogenetic therapy outperforms the effects of levetiracetam, indicating its potential to suppress drug-resistant seizures.

Auricular transcutaneous vagus nerve stimulation modulates the heart-evoked potential.

BACKGROUND: There is active interest in biomarker discovery for transcutaneous auricular vagus nerve stimulation (taVNS). However, greater understanding of the neurobiological mechanisms is needed to identify candidate markers. Accumulating evidence suggests that taVNS influences activity in solitary and parabrachial nuclei, the primary brainstem relays for the transmission of visceral sensory afferents to the insula. The insula mediates interoception, which concerns the representation and regulation of homeostatic bodily states. Consequently, interoceptive pathways may be relevant to taVNS mechanisms of action. HYPOTHESES: We hypothesized that taVNS would modulate an EEG-derived marker of interoceptive processing known as the heart-evoked potential (HEP). We also hypothesized that taVNS-induced HEP effects would be localizable to the insula. METHODS: Using a within-subject, sham-controlled design, we recorded EEG and ECG concurrent to taVNS in 43 healthy adults. Using ECG and EEG data, we extracted HEPs. Estimation of the cortical sources of the taVNS-dependent HEP responses observed at the scalp were computed using the Boundary Element Method and weighted Minimum Norm Estimation. Statistics were calculated using cluster-based permutation methods. RESULTS: taVNS altered HEP amplitudes at frontocentral and centroparietal electrode sites at various latencies. The taVNS-dependent HEP effect was localized to the insula, operculum, somatosensory cortex, and orbital and ventromedial prefrontal regions. CONCLUSION: The results support the hypothesis that taVNS can access the insula as well as functionally and anatomically connected brain regions. HEPs may serve as an objective, non-invasive outcome parameter for the cortical effects of taVNS.

Comparison of In Vivo and Ex Vivo Magnetic Resonance Imaging in a Rat Model for Glioblastoma-Associated Epilepsy.

Magnetic resonance imaging (MRI) is frequently used for preclinical treatment monitoring in glioblastoma (GB). Discriminating between tumors and tumor-associated changes is challenging on in vivo MRI. In this study, we compared in vivo MRI scans with ex vivo MRI and histology to estimate more precisely the abnormal mass on in vivo MRI. Epileptic seizures are a common symptom in GB. Therefore, we used a recently developed GB-associated epilepsy model from our group with the aim of further characterizing the model and making it useful for dedicated epilepsy research. Ten days after GB inoculation in rat entorhinal cortices, in vivo MRI (T2w and mean diffusivity (MD)), ex vivo MRI (T2w) and histology were performed, and tumor volumes were determined on the different modalities. The estimated abnormal mass on ex vivo T2w images was significantly smaller compared to in vivo T2w images, but was more comparable to histological tumor volumes, and might be used to estimate end-stage tumor volumes. In vivo MD images displayed tumors as an outer rim of hyperintense signal with a core of hypointense signal, probably reflecting peritumoral edema and tumor mass, respectively, and might be used in the future to distinguish the tumor mass from peritumoral edema-associated with reactive astrocytes and activated microglia, as indicated by an increased expression of immunohistochemical markers-in preclinical models. In conclusion, this study shows that combining imaging techniques using different structural scales can improve our understanding of the pathophysiology in GB.

Non-invasive vagal nerve stimulation enhances cognitive emotion regulation.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed as a potential new tool in the treatment of major depressive disorder. Prior studies have demonstrated that taVNS enhances cognitive control and is able to modulate brain activity in key regions involved in cognitive emotion regulation, such as the anterior cingulate and medial prefrontal cortex, which is known to be impaired in depressed patients. Preclinical studies are lacking but may provide important insights into the working mechanisms of taVNS on cognitive emotion regulatory processes. In this between-subject study, 83 healthy subjects underwent a single-session of active taVNS or sham stimulation, after which cognitive reappraisal was examined using a computer-based cognitive emotion regulation task. Our results indicate that participants receiving active taVNS, compared to sham, were better at using cognitive reappraisal and rated their response to emotion-eliciting pictures as less intense. Yet, even though we found significant differences in behavioral measures of cognitive emotion regulation, no differences between groups were found in terms of physiological responses to the emotional stimuli. Overall, these findings suggest a positive effect of taVNS on the cognitive reappraisal of emotions, but future studies assessing objective measures of neural activity during cognitive emotion regulation following taVNS are warranted.

Optimized Parameters for Transducing the Locus Coeruleus Using Canine Adenovirus Type 2 (CAV2) Vector in Rats for Chemogenetic Modulation Research.

INTRODUCTION: The locus coeruleus noradrenergic (LC-NA) system is studied for its role in various neurological and psychiatric disorders such as epilepsy and Major Depression Dissorder. Chemogenetics is a powerful technique for specific manipulation of the LC to investigate its functioning. Local injection of AAV2/7 viral vectors has limitations with regards to efficiency and specificity of the transduction, potentially due to low tropism of AAV2/7 for LC neurons. In this study we used a canine adenovirus type 2 (CAV2) vector with different volumes and viral particle numbers to achieve high and selective expression of hM3Dq, an excitatory Designer Receptor Exclusively Activated by Designer Drugs (DREADD), for chemogenetic modulation of LC neurons. METHODS: Adult male Sprague-Dawley rats were injected in the LC with different absolute numbers of CAV2-PRSx8-hM3Dq-mCherry physical particles (0.1E9, 1E9, 5E9,10E9, or 20E9 pp) using different volumes (LowV = 3 nl × 300 nl, MediumV = 3 × 600 nl, HighV = 3 × 1200 nl). Two weeks post-injection, double-labeling immunohistochemistry for dopamine ß hydroxylase (DBH) and mCherry was performed to determine hM3Dq expression and its specificity for LC neurons. The size of the transduced LC was compared to the contralateral LC to identify signs of toxicity. RESULTS: Administration of Medium volume (3 × 600 nl) and 1E9 particles resulted in high expression levels with 87.3 ± 9.8% of LC neurons expressing hM3Dq, but low specificity with 36.2 ± 17.3% of hM3Dq expression in non-LC neurons. The most diluted conditions (Low volume_0.1E pp and Medium Volume_0.1E pp) presented similar high transduction of LC neurons (70.9 ± 12.7 and 77.2 ± 9.8%) with lower aspecificity (5.5 ± 3.5 and 4.0 ± 1.9%, respectively). Signs of toxicity were observed in all undiluted conditions as evidenced by a decreased size of the transduced LC. CONCLUSION: This study identified optimal conditions (Low and Medium Volume with 0.1E9 particles of CAV2-PRSx8-hM3Dq-mCherry) for safe and specific transduction of LC neurons with excitatory DREADDs to study the role of the LC-NA system in health and disease.