Stimulation-evoked Responses Research Articles

Reliability of transcranial magnetic stimulation-evoked responses on knee extensor muscles during cycling.

Transcranial magnetic stimulation (TMS) measures the excitability and inhibition of corticomotor networks. Despite its task-specificity, few studies have used TMS during dynamic movements and the reliability of TMS paired pulses has not been assessed during cycling. This study aimed to evaluate the reliability of motor evoked potentials (MEP) and short- and long-interval intracortical inhibition (SICI and LICI) on vastus lateralis and rectus femoris muscle activity during a fatiguing single-leg cycling task. Nine healthy adults (2 female) performed two identical sessions of counterweighted single-leg cycling at 60% peak power output until failure. Five single pulses and ten paired pulses were delivered to the motor cortex, and two maximal femoral nerve stimulations (Mmax) were administered during two baseline cycling bouts (unfatigued) and every 5min throughout cycling (fatigued). When comparing both baseline bouts within the same session, MEP·Mmax-1 and LICI (both ICC: >0.9) were rated excellent while SICI was rated good (ICC: 0.7-0.9). At baseline, between sessions, in the vastus lateralis, Mmax (ICC: >0.9) and MEP·Mmax-1 (ICC: 0.7) demonstrated good reliability; LICI was moderate (ICC: 0.5), and SICI was poor (ICC: 0.3). Across the fatiguing task, Mmax demonstrated excellent reliability (ICC > 0.8), MEP·Mmax-1 ranged good to excellent (ICC: 0.7-0.9), LICI was moderate to excellent (ICC: 0.5-0.9), and SICI remained poorly reliable (ICC: 0.3-0.6). These results corroborate the cruciality of retaining mode-specific testing measurements and suggest that during cycling, Mmax, MEP·Mmax-1, and LICI measures are reliable whereas SICI, although less reliable across days, can be reliable within the same session.

Activity-dependent recruitment of inhibition and excitation in the awake mammalian cortex during electrical stimulation

Electrical stimulation is an effective tool for mapping and altering brain connectivity, with applications ranging from treating pharmacology-resistant neurological disorders to providing sensory feedback for neural prostheses. Paramount to the success of these applications is the ability to manipulate electrical currents to precisely control evoked neural activity patterns. However, little is known about stimulation-evoked responses in inhibitory neurons nor how stimulation-evoked activity patterns depend on ongoing neural activity. In this study, we used 2-photon imaging and cell-type specific labeling to measure single-cell responses of excitatory and inhibitory neurons to electrical stimuli in the visual cortex of awake mice. Our data revealed strong interactions between electrical stimulation and pre-stimulus activity of single neurons in awake animals and distinct recruitment and response patterns for excitatory and inhibitory neurons. This work demonstrates the importance of cell-type-specific labeling of neurons in future studies.

Hyperexcitability in the Olfactory Bulb and Impaired Fine Odor Discrimination in the Fmr1 KO Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders (ASDs) in humans. FXS is caused by loss of expression of the fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here, we conducted experiments in wild-type (WT) and Fmr1 knock-out (KO; Fmr1-/y ) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) in Fmr1 KO mice displayed greatly enhanced excitation under baseline conditions, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of spontaneous LLDs (sLLDs), which appeared to be because of a decrease in GABAergic synaptic inhibition in glomeruli leading to more feedforward excitation, caused a reduction in the reliability of stimulation-evoked responses in MCs. In addition, in a go/no-go operant discrimination paradigm, we found that Fmr1 KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the Fmr1 KO-induced reduction in MC response reliability is one plausible mechanism for the impaired fine odor discrimination.SIGNIFICANCE STATEMENT Fragile X syndrome (FXS) in humans is associated with a range of debilitating deficits including aberrant sensory processing. One sensory system that has received comparatively little attention in studies in animal models of FXS is olfaction. Here, we report the first comprehensive physiological analysis of circuit defects in the olfactory bulb in the commonly-used Fmr1 knock-out (KO) mouse model of FXS. Our studies indicate that Fmr1 KO alters the local excitation/inhibition balance in the bulb, similar to what Fmr1 KO does in other brain circuits, but through a novel mechanism that involves enhanced feedforward excitation. Furthermore, Fmr1 KO mice display behavioral impairments in fine odor discrimination, an effect that may be explained by changes in neural response reliability.

Low-frequency deep brain stimulation reveals resonant beta-band evoked oscillations in the pallidum of Parkinson's Disease patients.

Evidence suggests that spontaneous beta band (11-35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson's disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined. We characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery. Our analyses show that low-frequency (2-4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization. Our results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

Development of abnormalities at the neuromuscular junction in the SOD1-G93A mouse model of ALS: dysfunction then disruption of postsynaptic structure precede overt motor symptoms.

The ultimate deficit in amyotrophic lateral sclerosis (ALS) is neuromuscular junction (NMJ) loss, producing permanent paralysis, ultimately in respiratory muscles. However, understanding the functional and structural deficits at NMJs prior to this loss is crucial for therapeutic strategy design. Should early interventions focus on reversing denervation, or supporting largely intact NMJs that are functionally impaired? We therefore determined when functional and structural deficits appeared in diaphragmatic NMJs relative to the onset of hindlimb tremor (the first overt motor symptoms) in vivo in the SOD1-G93A mouse model of ALS. We employed electrophysiological recording of NMJ postsynaptic potentials for spontaneous and nerve stimulation-evoked responses. This was correlated with fluorescent imaging microscopy of the postsynaptic acetylcholine receptor (AChR) distribution throughout the postnatal developmental timecourse from 2 weeks to early symptomatic ages. Significant reduction in the amplitudes of spontaneous miniature endplate potentials (mEPPs) and evoked EPPs emerged only at early symptomatic ages (in our colony, 18-22 weeks). Reductions in mEPP frequency, number of vesicles per EPP, and EPP rise time were seen earlier, at 16weeks, but this reversed by early symptomatic ages. However, the earliest and most striking impairment was an inability to maintain EPP amplitude during a 20 Hz stimulus train, which appeared 6 weeks before overt in vivo motor symptoms. Despite this, fluorescent α-bungarotoxin labelling revealed no systematic, progressive changes in 11 comprehensive NMJ morphological parameters (area, shape, compactness, number of acetylcholine receptor, AChR, regions, etc.) with disease progression. Rather, while NMJs were largely normally-shaped, from 16 weeks there was a progressive and substantial disruption in AChR concentration and distribution within the NMJ footprint. Thus, NMJ functional deficits appear at least 6 weeks before motor symptoms in vivo, while structural deficits occur 4 weeks later, and predominantly within NMJs. These data suggest initial therapies focused on rectifying suboptimal NMJ function could produce effective relief of symptoms of weakness.

Meta-analysis of the effects of anti-migraine therapeutics in the rat trigeminovascular nociception model as a tool for design optimization.

The main reasons for the low reliability of results from preclinical studies are the lack of prior sample size calculations and poor experimental design. Here, we demonstrate how the tools of meta-analysis can be implemented to tackle these issues. We conducted a systematic search to identify controlled studies testing established migraine treatments in the electrophysiological model of trigeminovascular nociception (EMTVN). Drug effects on the two outcomes, dural stimulation-evoked responses and ongoing neuronal activity were analyzed separately using a three-level model with robust variance estimation. According to the meta-analysis, which included 21 experiments in rats reported in 13 studies, these drugs significantly reduced trigeminovascular nociceptive traffic, affecting both outcomes. Based on the estimated effect sizes and outcome variance, we provide guidance on sample sizes allowing to detect such effects with sufficient power in future experiments. Considering the revealed methodological features that potentially influence the results and the main source of statistical bias of the included studies, we discuss the translational potential of the EMTVN and the steps needed to improve it. We believe that the presented approach can be used for design optimization in research with other animal models and as such deserves further validation.

Mapping Spinal Cord Stimulation-Evoked Muscle Responses in Patients With Chronic Spinal Cord Injury

ObjectivesEpidural spinal cord stimulation (eSCS) has shown promise for restoring some volitional motor control after spinal cord injury (SCI). Maximizing therapeutic response requires effective spatial stimulation generated through careful configuration of anodes and cathodes on the eSCS lead. By exploring the way the spatial distribution of low frequency stimulation affects muscle activation patterns, we investigated the spatial specificity of stimulation-evoked responses for targeted muscle groups for restoration after chronic SCI (cSCI) in participants in the Epidural Stimulation After Neurologic Damage (E-STAND) trial. Materials and MethodsFifteen participants with Abbreviated Injury Scale A cSCI from the E-STAND study were evaluated with a wide range of bipolar spatial patterns. Surface electromyography captured stimulation-evoked responses from the rectus abdominis (RA), intercostal, paraspinal, iliopsoas, rectus femoris (RF), tibialis anterior (TA), extensor hallucis longus (EHL), and gastrocnemius muscle groups bilaterally. Peak-to-peak amplitudes were analyzed for each pulse across muscles. Stimulation patterns with dipoles parallel (vertical configurations), perpendicular (horizontal configurations), and oblique (diagonal configurations) relative to the rostral-caudal axis were evaluated. ResultsCathodic stimulation in the transverse plane indicated ipsilaterally biased activation in RA, intercostal, paraspinal, iliopsoas, RF, TA, EHL, and gastrocnemius muscles (p < 0.05). We found that caudal cathodic stimulation was significantly more activating only in the RF and EHL muscle groups than in the rostral (p < 0.037 and p < 0.006, respectively). Oblique stimulation was found to be more activating in the RA, intercostal, paraspinal, iliopsoas, and TA muscle groups than in the transverse (p < 0.05). ConclusionsCathodic stimulation provides uniform specificity for targeting laterality. Few muscle groups responded specifically to variation in rostral/caudal stimulation, and oblique stimulation improved stimulation responses when compared with horizontal configurations. These relations may enable tailored targeting of muscle groups, but the surprising amount of variation observed suggests that monitoring these evoked muscle responses will play a key role in this tailoring process. Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT03026816.

Localizing seizure onset zones in surgical epilepsy with neurostimulation deep learning.

In drug-resistant temporal lobe epilepsy, automated tools for seizure onset zone (SOZ) localization that use brief interictal recordings could supplement presurgical evaluations and improve care. Thus, the authors sought to localize SOZs by training a multichannel convolutional neural network on stereoelectroencephalography (SEEG) cortico-cortical evoked potentials. The authors performed single-pulse electrical stimulation in 10 drug-resistant temporal lobe epilepsy patients implanted with SEEG. Using 500,000 unique poststimulation SEEG epochs, the authors trained a multichannel 1-dimensional convolutional neural network to determine whether an SOZ had been stimulated. SOZs were classified with mean sensitivity of 78.1% and specificity of 74.6% according to leave-one-patient-out testing. To achieve maximum accuracy, the model required a 0- to 350-msec poststimulation time period. Post hoc analysis revealed that the model accurately classified unilateral versus bilateral mesial temporal lobe seizure onset, as well as neocortical SOZs. This was the first demonstration, to the authors' knowledge, that a deep learning framework can be used to accurately classify SOZs with single-pulse electrical stimulation-evoked responses. These findings suggest that accurate classification of SOZs relies on a complex temporal evolution of evoked responses within 350 msec of stimulation. Validation in a larger data set could provide a practical clinical tool for the presurgical evaluation of drug-resistant epilepsy.

Advanced Technology for the Conversion of Waste into Fuels and Chemicals

Nicotinic acetylcholine receptors are cationic channels that mediate fast excitatory transmission in the central nervous system. Several nicotinic acetylcholine receptor subunits have been detected within cerebellar granule cell layer (GCL), and activation of these receptors may have a significant influence on neuronal synaptic transmission of the cerebellum. The aim of present study was to better understand the roles of nicotinic acetylcholine receptors during the sensory stimulation-evoked synaptic transmission in the cerebellar GCL. Our results showed that cerebellar surface perfusion of nicotine significantly facilitated the cerebellar GCL field potential responses evoked by air-puff stimulation of ipsilateral whisker pad, which exhibited increases in amplitude and area under the curve (AUC) of both stimulus onset responses (N1) and stimulus offset responses (N2). The nicotine-induced increase in AUC of facial stimulation-evoked N1 was dose-dependent with a 50% effective concentration (EC50) of 32.6 μM. Application of either a selective α4β2 nicotinic acetylcholine receptors antagonist, DHβE (1 μM) or a selective α7 nicotinic acetylcholine receptors antagonist, MLA (1 μM) alone attenuated, but not completely abolished the nicotine-induced increases in the amplitude and AUC of the facial stimulation-evoked N1. However, simultaneous blockade of α7 and α4β2 nicotinic acetylcholine receptor subunits abolished the nicotine-induced increase in the amplitude of N1. These results indicate that nicotine activates α7 and α4β2 nicotinic acetylcholine receptor subunits, resulting in an enhancement of facial stimulation-evoked responses in mouse cerebellar GCL. Our results suggest that nicotine modulates the sensory information processing in the cerebellar GCL through α7 and α4β2 subunits nicotinic acetylcholine receptors.

Frequency distribution in intraoperative stimulation-evoked EMG responses during selective dorsal rhizotomy in children with cerebral palsy\u2014part 2: gender differences and left-biased asymmetry

IntroductionSpinal reflexes reorganize in cerebral palsy (CP), producing hyperreflexia and spasticity. CP is more common among male infants, and gender might also influence brain and spinal–cord reorganization. This retrospective study investigated the frequency of higher-graded EMG responses elicited by electrical nerve–root stimulation during selective dorsal rhizotomy (SDR), prior to partial nerve– root deafferentation, considering not only segmental level and body side, but also gender.MethodsIntraoperative neuromonitoring (IOM) was used in SDR to pinpoint the rootlets most responsible for exacerbated stimulation-evoked EMG patterns recorded from lower-limb muscle groups. Responses were graded according to an objective response-classification system, ranging from no abnormalities (grade 0) to highly abnormal (grade 4+), based on ipsilateral spread and contralateral involvement. Non-parametric analysis of data with repeated measures was primarily used in investigating the frequency distribution of these various EMG response grades. Over 7000 rootlets were stimulated, and the results for 65 girls and 81 boys were evaluated, taking changes in the composition of patient groups into account when considering GMFCS levels.ResultsThe distribution of graded EMG responses varied according to gender, laterality, and level. Higher-graded EMG responses were markedly more frequent in the boys and at lower segmental levels (L5, S1). Left-biased asymmetry in higher–graded rootlets was also more noticeable in the boys and in patients with GMFCS level I. A close link was observed between higher-grade assessments and left-biased asymmetry.ConclusionsDetailed insight into the patient’s initial spinal-neurofunctional state prior to deafferentation suggests that differences in asymmetrical spinal reorganization might be attributable to a hemispheric imbalance.

Frequency distribution in intraoperative stimulation-evoked EMG responses during selective dorsal rhizotomy in children with cerebral palsy\u2014part 1: clinical setting and neurophysiological procedure

IntroductionSelective dorsal rhizotomy (SDR) consists of microsurgical partial deafferentation of sensory nerve roots (L1–S2). It is primarily used today in decreasing spasticity in young cerebral palsy (CP) patients. Intraoperative monitoring (IOM) is an essential part of the surgical decision-making process, aimed at improving functional results. The role played by SDR-IOM is examined, while realizing that connections between complex EMG responses to nerve–root stimulation and a patient’s individual motor ability remain to be clarified.MethodsWe conducted this retrospective study, analyzing EMG responses in 146 patients evoked by dorsal–root and rootlet stimulation, applying an objective response–classification system, and investigating the prevalence and distribution of the assessed grades. Part1 describes the clinical setting and SDR procedure, reintroduced in Germany by the senior author in 2007.ResultsStimulation-evoked EMG response patterns revealed significant differences along the segmental levels. More specifically, a comparison of grade 3+4 prevalence showed that higher-graded rootlets were more noticeable at lower nerve root levels (L5, S1), resulting in a typical rostro-caudal anatomical distribution.ConclusionsIn view of its prophylactic potential, SDR should be carried out at an early stage in all CP patients suffering from severe spasticity. It is particularly effective when used as an integral part of a coordinated, comprehensive spasticity program in which a team of experts pool their information. The IOM findings pertaining to the anatomical grouping of grades could be of potential importance in adjusting the SDR-IOM intervention to suit the specific individual constellation, pending further validation.Trial registrationClinicalTrials.gov ID: NCT03079362

Excitatory/Inhibitory Responses Shape Coherent Neuronal Dynamics Driven by Optogenetic Stimulation in the Primate Brain.

Coherent neuronal dynamics play an important role in complex cognitive functions. Optogenetic stimulation promises to provide new ways to test the functional significance of coherent neural activity. However, the mechanisms by which optogenetic stimulation drives coherent dynamics remain unclear, especially in the nonhuman primate brain. Here, we perform computational modeling and experiments to study the mechanisms of optogenetic-stimulation-driven coherent neuronal dynamics in three male nonhuman primates. Neural responses arise from stimulation-evoked, temporally dynamic excitatory (E) and inhibitory (I) activity. Spiking activity is more likely to occur during E/I imbalances. Thus the relative difference in the driven E and I responses precisely controls spike timing by forming a brief time interval of increased spiking likelihood. Experimental results agree with parameter-dependent predictions from the computational models. These results demonstrate that optogenetic stimulation driven coherent neuronal dynamics are governed by the temporal properties of E/I activity. Transient imbalances in excitatory and inhibitory activity may provide a general mechanism for generating coherent neuronal dynamics without the need for an oscillatory generator.SIGNIFICANCE STATEMENT We examine how coherent neuronal dynamics arise from optogenetic stimulation in the primate brain. Using computational models and experiments, we demonstrate that coherent spiking and local field potential activity is generated by stimulation-evoked responses of excitatory and inhibitory activity in networks, extending the growing literature on neuronal dynamics. These responses create brief time intervals of increased spiking tendency and are consistent with previous observations in the literature that balanced excitation and inhibition controls spike timing, suggesting that optogenetic-stimulation-driven coherence may arise from intrinsic E/I balance. Most importantly, our results are obtained in nonhuman primates and thus will play a leading role in driving the use of causal manipulations with optogenetic tools to study higher cognitive functions in the primate brain.

Chronic ethanol exposure facilitates facial-evoked MLI-PC synaptic transmission via nitric oxide signaling pathway in vivo in mice

Ethanol (EtOH) exposure causes alterations of motor coordination, balance, behavior, speech, and certain cognitive functions are considered to be caused partly by impairment of cerebellar circuits function and modulation of synaptic transmission. The cerebellar cortical molecular layer interneuron-Purkinje cell (MLI-PC) synapses are critical for various information integration and transmission, which are sensitive to acute and chronic EtOH exposure. The aim of this study is to investigate the effect of chronic ethanol exposure on the facial stimulation-evoked MLI-PC synaptic transmission in urethane-anesthetized mice, by electrophysiological recording and pharmacological methods. Under current-clamp recording conditions, air-puff stimulation of ipsilateral whisker pad evoked MLI-PC synaptic transmission, which expressed an inhibitory component (P1) followed by a pause of simple spike (SS) firing in cerebellar PCs. Chronic ethanol exposure did not change the latency of the facial stimulation-evoked responses in cerebellar PCs, but induced significant enhancement of the stimulation-evoked MLI-PC synaptic transmission, which expressed increases in amplitude of P1 and pause of SS firing. The amplitude of P1 and pause of SS in ethanol exposure group were significant higher than that in control group. Cerebellar surface application of nitric oxide synthesis (NOS) inhibitor, L-NNA (5 mM) significantly decreased the amplitude of P1 and the pause of SS firing in EtOH exposure group, but did no effect on control group. In contrast, cerebellar surface application of NO donor, SNAP (100 μM) significantly increased the amplitude of P1 and the pause of SS firing in control group, but not in EtOH exposure group. These results indicated that chronic EtOH exposure significantly facilitated the sensory-evoked MLI-PC synaptic transmission via NO signaling pathway in mouse cerebellar cortex

Deep Brain Stimulation for Epilepsy: Biomarkers for Optimization.

Two large-scale controlled clinical trials have provided Class I evidence for the benefit of deep brain stimulation (DBS) as a therapy for refractory epilepsy. However, the efficacy has been variable, with some patients not achieving any improvement in their seizure control. This disparity could be the result of suboptimal stimulation parameters/electrodes or alternatively a difference in the type of seizures being treated. This review presents the most recent clinical results with a focus on two major targets for DBS, the anterior nucleus of the thalamus (ANT) and the hippocampus. We detail the etiologies where DBS might work best, and provide evidence for the use of recorded neural responses for the optimization of stimulation parameters and closed-loop control of devices. Stimulation of the hippocampus may work well for both focal and generalized seizures, whereas ANT stimulation may be best for focal seizures only. Studies have demonstrated that changes in stimulation-evoked response shape can be used as a biomarker for stimulation efficacy. Furthermore, new biomarkers have been identified that could be used for closed-loop stimulation. Improvements in patient screening and stimulation optimization are needed for patients to achieve optimal seizure control. Furthermore, therapy should be adjusted to suit individual patient needs. Recording evoked responses during the application of DBS could be used to measure the effectiveness of DBS and titrate stimulation as needed.

Etomidate Modulates the Tactile Stimulation-Evoked Field Potential Responses in Cerebellar Granule Cell Layer in vivo in Mice

Etomidate (ET) produces sedation by binding on the γ-aminobutyric acid type A (GABAA) receptors. We previously found that ET inhibited cerebellar Purkinje cells activity via both GABAA and glycine receptors in vivo in mice, suggesting that ET modulated sensory information synaptic transmission in cerebellar cortex. In this study, we investigated the effect of ET on the sensory stimulation-evoked responses in the cerebellar granule layer (GL) in urethane-anesthetized mice, using electrophysiological and pharmacological methods. Our results showed that cerebellar surface perfusion of ET (100 μmol/L) significantly decreased amplitude and area under the curve (AUC) of the sensory stimulation-evoked excitatory component (N1) in the cerebellar GL. Application of GABAA receptor antagonist, SR95531 (20 μmol/L) significantly attenuated, but not abolished the ET-induced decrease in amplitude and AUC of facial stimulation-evoked responses. However, application of a mixture of SR95531 (20 μmol/L) and cannabinoid 1 receptor (CB1) antagonist, AM-251 (5 μmol/L), completely blocked the ET-induced decrease in amplitude and AUC of facial stimulation-evoked responses. Furthermore, application of the CB1 receptor agonist, WIN55212-2, induced a decrease in amplitude and AUC of N1 in the absence of GABAA receptors activity, as well occluded the ET-induced depression of N1. Moreover, the ET-induced changes in amplitude and AUC of N1 in absence of GABAA receptors activity were abolished by a specific protein kinase A (PKA) inhibitor, KT5720. These results indicate that ET facilitates CB1 receptors in the absence of GABAA receptors activity, resulting in a depression of the sensory stimulation-evoked synaptic transmission via PKA signaling pathway in mouse cerebellar GL.

Microstimulation-induced inhibition of thalamic reticular nucleus in non-human primates.

The thalamic reticular nucleus (TRN) modulates activity in the thalamus and controls excitatory input from corticothalamic and thalamocortical glutamatergic projections. It is made up of GABAergic neurons which project topographically to the thalamus. The TRN also receives inhibitory projections from the globus pallidus and the substantia nigra pars reticulata. Photostimulation of the TRN results in local inhibition in rat slice preparations but the effects of local stimulation in vivo are not known. This study aimed to characterize stimulation-evoked responses in the TRN of non-human primates (NHPs). Microelectrodes were inserted into the TRN and neurons were stimulated at 5, 10, 15, and 20µA using 0.5s trains at 100Hz and the subsequent response was recorded from the same electrode. Stimulation in surrounding nuclei and the internal capsule was used for mapping the anatomical borders of the TRN. Stimulation as low as 10µA resulted in predominantly inhibition, recorded in both single units and background unit activity (BUA). The duration of inhibition (~ 1-3s) increased with increasing stimulation amplitude and was significantly increased in BUA when single units were present. At 20µA of current, 93% of the single units (41/44) and 92% of BUA sites (67/73) were inhibited. Therefore, microstimulation of the NHP TRN with low currents results in current-dependent inhibition of single units and BUA. This finding may be useful to further aid in localization of deep thalamic and subthalamic nuclei during brain surgery.

Nicotine modulates the facial stimulation-evoked responses in cerebellar granule cell layer in vivo in mice

Nicotinic acetylcholine receptors are cationic channels that mediate fast excitatory transmission in the central nervous system. Several nicotinic acetylcholine receptor subunits have been detected within cerebellar granule cell layer (GCL), and activation of these receptors may have a significant influence on neuronal synaptic transmission of the cerebellum. The aim of present study was to better understand the roles of nicotinic acetylcholine receptors during the sensory stimulation-evoked synaptic transmission in the cerebellar GCL. Our results showed that cerebellar surface perfusion of nicotine significantly facilitated the cerebellar GCL field potential responses evoked by air-puff stimulation of ipsilateral whisker pad, which exhibited increases in amplitude and area under the curve (AUC) of both stimulus onset responses (N1) and stimulus offset responses (N2). The nicotine-induced increase in AUC of facial stimulation-evoked N1 was dose-dependent with a 50% effective concentration (EC50) of 32.6 μM. Application of either a selective α4β2 nicotinic acetylcholine receptors antagonist, DHβE (1 μM) or a selective α7 nicotinic acetylcholine receptors antagonist, MLA (1 μM) alone attenuated, but not completely abolished the nicotine-induced increases in the amplitude and AUC of the facial stimulation-evoked N1. However, simultaneous blockade of α7 and α4β2 nicotinic acetylcholine receptor subunits abolished the nicotine-induced increase in the amplitude of N1. These results indicate that nicotine activates α7 and α4β2 nicotinic acetylcholine receptor subunits, resulting in an enhancement of facial stimulation-evoked responses in mouse cerebellar GCL. Our results suggest that nicotine modulates the sensory information processing in the cerebellar GCL through α7 and α4β2 subunits nicotinic acetylcholine receptors.

Blockade of 5-HT3 receptors with granisetron does not affect trigeminothalamic nociceptive transmission in rats: Implication for migraine.

One way to expand the existing range of anti-migraine drugs seems to be the search for pharmacological agents with anti-cephalalgic properties among medicines approved for clinical indications other than migraine. Numerous experimental and clinical data imply that selective serotonin 5-HT3 receptor antagonists can be considered as potential anti-migraine agents. Therefore, the objective of our work was to examine the impact of selective 5-HT3 receptor blockade with granisetron on migraine-related nociceptive transmission within the spinal trigeminal nucleus (STN) and the ventroposteromedial nucleus of the thalamus (VPM). Using an electrophysiological model of trigemino-durovascular nociception in anaesthetised male Wistar rats, we evaluated the effects of intravenous administration of granisetron on ongoing firing and dural electrical stimulation-evoked responses of the spinal trigeminal and thalamic cells. Granisetron did not substantially affect responses of the STN and VPM neurons to electrical stimulation of the dura mater as well as did not cause steady changes in ongoing firing of the spinal trigeminal cells. The results obtained argue against the use of 5-HT3 receptor antagonists for treating migraine. These data also lead to the conclusion that in the absence of sustained sensitisation of neurons along the trigemino-thalamo-cortical pathway the role of 5-HT3 receptor-dependent mechanisms in serotonergic modulation of trigeminovascular nociceptive transmission can hardly be considered crucial.

Roles of N-methyl-d-aspartate receptors during the sensory stimulation-evoked field potential responses in mouse cerebellar cortical molecular layer.

The functions of N-methyl-d-aspartate receptors (NMDARs) in cerebellar cortex have been widely studied under in vitro condition, but their roles during the sensory stimulation-evoked responses in the cerebellar cortical molecular layer in living animals are currently unclear. We here investigated the roles of NMDARs during the air-puff stimulation on ipsilateral whisker pad-evoked field potential responses in cerebellar cortical molecular layer in urethane-anesthetized mice by electrophysiological recording and pharmacological methods. Our results showed that cerebellar surface administration of NMDA induced a dose-dependent decrease in amplitude of the facial stimulation-evoked inhibitory responses (P1) in the molecular layer, accompanied with decreases in decay time, half-width and area under curve (AUC) of P1. The IC50 of NMDA induced inhibition in amplitude of P1 was 46.5μM. In addition, application of NMDA induced significant increases in the decay time, half-width and AUC values of the facial stimulation-evoked excitatory responses (N1) in the molecular layer. Application of an NMDAR blocker, D-APV (250μM) abolished the facial stimulation-evoked P1 in the molecular layer. These results suggested that NMDARs play a critical role during the sensory information processing in cerebellar cortical molecular layer in vivo in mice.

A micro-scale printable nanoclip for electrical stimulation and recording in small nerves

Objective. The vision of bioelectronic medicine is to treat disease by modulating the signaling of visceral nerves near various end organs. In small animal models, the nerves of interest can have small diameters and limited surgical access. New high-resolution methods for building nerve interfaces are desirable. In this study, we present a novel nerve interface and demonstrate its use for stimulation and recording in small nerves. Approach. We design and fabricate micro-scale electrode-laden nanoclips capable of interfacing with nerves as small as 50 µm in diameter. The nanoclips are fabricated using a direct laser writing technique with a resolution of 200 nm. The resolution of the printing process allows for incorporation of a number of innovations such as trapdoors to secure the device to the nerve, and quick-release mounts that facilitate keyhole surgery, obviating the need for forceps. The nanoclip can be built around various electrode materials; here we use carbon nanotube fibers for minimally invasive tethering. Main results. We present data from stimulation-evoked responses of the tracheal syringeal (hypoglossal) nerve of the zebra finch, as well as quantification of nerve functionality at various time points post implant, demonstrating that the nanoclip is compatible with healthy nerve activity over sub-chronic timescales. Significance. Our nerve interface addresses key challenges in interfacing with small nerves in the peripheral nervous system. Its small size, ability to remain on the nerve over sub-chronic timescales, and ease of implantation, make it a promising tool for future use in the treatment of disease.