Afferent Volley Research Articles

Investigating the effects of dopamine on short- and long-latency afferent inhibition.

Short- and long-latency afferent inhibition (SAI and LAI respectively) are phenomenon whereby the motor evoked potential induced by transcranial magnetic stimulation (TMS) is inhibited by a sensory afferent volley consequent to nerve stimulation. It remains unclear whether dopamine participates in the genesis or modulation of SAI and LAI. The present study aimed to determine if SAI and LAI are modulated by levodopa (l-DOPA). In this placebo-controlled, double-anonymized study Apo-Levocarb (100mg l-DOPA in combination with 25mg carbidopa) and a placebo were administered to 32 adult males (mean age 24±3 years) in two separate sessions. SAI and LAI were evoked by stimulating the median nerve and delivering single-pulse TMS over the motor hotspot corresponding to the first dorsal interosseous muscle of the right hand. SAI and LAI were quantified before and 1h following ingestion of drug or placebo corresponding to the peak plasma concentration of Apo-Levocarb. The results indicate that Apo-Levocarb increases SAI and does not significantly alter LAI. These findings support literature demonstrating increased SAI following exogenous dopamine administration in neurodegenerative disorders. KEY POINTS: Short- and long-latency afferent inhibition (SAI and LAI respectively) are measures of corticospinal excitability evoked using transcranial magnetic stimulation. SAI and LAI are reduced in conditions such as Parkinson's disease which suggests dopamine may be involved in the mechanism of afferent inhibition. 125mg of Apo-Levocarb (100mg dopamine) increases SAI but not LAI. This study increases our understanding of the pharmacological mechanism of SAI and LAI.

Suppression of perceptual sensitivity to digital nerve stimulation induced by afferent volley from digital nerve of contralateral homologous finger.

The purpose of the present study is to investigate whether perceptual sensitivity to digital nerve stimulation is modulated by the afferent volley from the digital nerve of a contralateral finger. Fifteen healthy humans participated in this study. A test stimulus was given to the right-hand index finger, and a conditioning stimulus was given to one of the five fingers on the left hand 20, 30, or 40 ms before the test stimulus. The perceptual threshold of the finger stimulation was measured. The perceptual threshold of the test stimulus was significantly increased by a conditioning stimulus to the left-hand index finger given 40 ms before the test stimulus. In contrast, the threshold was not significantly changed by a conditioning stimulus to any finger other than the index finger. Perceptual sensitivity to digital nerve stimulation is suppressed by the afferent volley from the digital nerve of the contralateral homologous finger. This means that the afferent volley from the digital nerve suppresses the homologous finger representation in the ipsilateral somatosensory areas. These findings can be explained by the view that the afferent volley from the digital nerve of the index finger projects to the index finger representation in the contralateral primary sensory cortex and that the interhemispheric transcallosal inhibitory drive is provided from the secondary sensory cortex to the homologous finger representation in the contralateral secondary sensory cortex.

Combined Peripheral Nerve Stimulation and Controllable Pulse Parameter Transcranial Magnetic Stimulation to Probe Sensorimotor Control and Learning.

Skilled motor ability depends on efficiently integrating sensory afference into the appropriate motor commands. Afferent inhibition provides a valuable tool to probe the procedural and declarative influence over sensorimotor integration during skilled motor actions. This manuscript describes the methodology and contributions of short-latency afferent inhibition (SAI) for understanding sensorimotor integration. SAI quantifies the effect of a convergent afferent volley on the corticospinal motor output evoked by transcranial magnetic stimulation (TMS). The afferent volley is triggered by the electrical stimulation of a peripheral nerve. The TMS stimulus is delivered to a location over the primary motor cortex that elicits a reliable motor-evoked response in a muscle served by that afferent nerve. The extent of inhibition in the motor-evoked response reflects the magnitude of the afferent volley converging on the motor cortex and involves central GABAergic and cholinergic contributions. The cholinergic involvement in SAI makes SAI a possible marker of declarative-procedural interactions in sensorimotor performance and learning. More recently, studies have begun manipulating the TMS current direction in SAI to tease apart the functional significance of distinct sensorimotor circuits in the primary motor cortex for skilled motor actions. The ability to control additional pulse parameters (e.g., the pulse width) with state-of-the-art controllable pulse parameter TMS (cTMS) has enhanced the selectivity of the sensorimotor circuits probed by the TMS stimulus and provided an opportunity to create more refined models of sensorimotor control and learning. Therefore, the current manuscript focuses on SAI assessment using cTMS. However, the principles outlined here also apply to SAI assessed using conventional fixed pulse width TMS stimulators and other forms of afferent inhibition, such as long-latency afferent inhibition (LAI).

Afferent volley from the digital nerve induces short-latency facilitation of perceptual sensitivity and primary sensory cortex excitability.

The present study examined whether the perceptual sensitivity and excitability of the primary sensory cortex are modulated by the afferent volley from the digital nerve of a conditioned finger within a short period of time. The perceptual threshold of an electrical stimulus to the index finger (test stimulus) was decreased by a conditioning stimulus to the index finger 4 or 6ms before the test stimulus, or by a stimulus to the middle or ring finger 2ms before that. This is explained by the view that the afferent volleys from the digital nerves of the fingers converge in the somatosensory areas, causing spatial summation of the afferent inputs through a small number of synaptic relays, leading to the facilitation of perceptual sensitivity. The N20 component of the somatosensory-evoked potential was facilitated by a conditioning stimulus to the middle finger 4ms before a test stimulus or to the thumb 2ms before the test stimulus. This is explained by the view that the afferent volley from the digital nerve of the finger adjacent to the tested finger induces lateral facilitation of the representation of the tested finger in the primary sensory cortex through a small number of synaptic relays.

Diaphragm stimulation elicits phrenic afferent-induced neuromuscular plasticity

We hypothesized that activation of phrenic afferents induces diaphragm motor plasticity. In anesthetized and spontaneously breathing rats we delivered 40 Hz, low threshold (twitch and 1.5X twitch threshold), inspiratory-triggered stimulation to the left hemidiaphragm for 30 min to activate ipsilateral phrenic afferents. Diaphragm amplitude ipsilateral and contralateral to stimulation were increased for 60 min following both currents compared to time controls not receiving stimulation. Diaphragm stimulation was repeated in laminectomy controls or following a unilateral C3-C6 dorsal rhizotomy to eliminate phrenic afferent volleys. Laminectomy controls expressed neuromuscular plasticity post-stimulation. In contrast, ipsilateral and contralateral diaphragm amplitude following dorsal rhizotomy was lower than laminectomy controls and no different than time controls, suggesting diaphragm motor plasticity was not induced post-rhizotomy. Our results indicate that diaphragm stimulation induces a novel form of plasticity in the phrenic motor system which requires phrenic afferent activation. Respiratory motor plasticity elicited by diaphragm stimulation may have value as a therapeutic strategy to improve diaphragm output in neuromuscular conditions.

Temporal Profile of Descending Cortical Modulation of Spinal Excitability: Group and Individual-Specific Effects.

Sensorimotor control is modulated through complex interactions between descending corticomotor pathways and ascending sensory inputs. Pairing sub-threshold transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS) modulates the Hoffmann’s reflex (H-reflex), providing a neurophysiologic probe into the influence of descending cortical drive on spinal segmental circuits. However, individual variability in the timing and magnitude of H-reflex modulation is poorly understood. Here, we varied the inter-stimulus interval (ISI) between TMS and PNS to systematically manipulate the relative timing of convergence of descending TMS-induced volleys with respect to ascending PNS-induced afferent volleys in the spinal cord to: (1) characterize effective connectivity between the primary motor cortex (M1) and spinal circuits, mediated by both direct, fastest-conducting, and indirect, slower-conducting descending pathways; and (2) compare the effect of individual-specific vs. standard ISIs. Unconditioned and TMS-conditioned H-reflexes (24 different ISIs ranging from −6 to 12 ms) were recorded from the soleus muscle in 10 able-bodied individuals. The magnitude of H-reflex modulation at individualized ISIs (earliest facilitation delay or EFD and individual-specific peak facilitation) was compared with standard ISIs. Our results revealed a significant effect of ISI on H-reflex modulation. ISIs eliciting earliest-onset facilitation (EFD 0 ms) ranged from −3 to −5 ms across individuals. No difference in the magnitude of facilitation was observed at EFD 0 ms vs. a standardized short-interval ISI of −1.5 ms. Peak facilitation occurred at longer ISIs, ranging from +3 to +11 ms. The magnitude of H-reflex facilitation derived using an individual-specific peak facilitation was significantly larger than facilitation observed at a standardized longer-interval ISI of +10 ms. Our results suggest that unique insights can be provided with individual-specific measures of top-down effective connectivity mediated by direct and/or fastest-conducting pathways (indicated by the magnitude of facilitation observed at EFD 0 ms) and other descending pathways that encompass relatively slower and/or indirect connections from M1 to spinal circuits (indicated by peak facilitation and facilitation at longer ISIs). By comprehensively characterizing the temporal profile and inter-individual variability of descending modulation of spinal reflexes, our findings provide methodological guidelines and normative reference values to inform future studies on neurophysiological correlates of the complex array of descending neural connections between M1 and spinal circuits.

Individual Difference in Cooperation and Reciprocal Choice: Findings From the Prisoner’s Dilemma

Following nociceptive heat or laser stimulation, an early contralateral and later vertex potential can be recorded. Although more indicative of the nociceptive input, the acquisition of the contralateral N1 after contact heat stimulation (contact heat-evoked potentials [CHEPs]) remains difficult. An advantage of contact heat is that the baseline skin temperature preceding peak stimulation can be controlled. Increasing the baseline temperature may represent a novel strategy to improve the acquisition of CHEPs without resulting in more subjective pain to stimulation. A study was undertaken in 23 healthy subjects to examine the effects of increasing the baseline temperature but not the perceived intensity of contact heat stimulation. A combined standard averaging and single-trial analysis was performed to disclose how changes in averaged waveforms related to latency jitter and individual trial amplitudes. By increasing the baseline temperature, the acquisition of N1 was improved among subjects with a low-amplitude response (greater than −4 μV) following 35°C baseline temperature stimulation (P < .05). Based on standard averaging, N2/P2 amplitudes were also significantly increased with and without an accompanying change in the rating of perceived pain when the baseline temperature was increased (P < .05). In contrast, automated single-trial averaging revealed no significant difference in N2 amplitude when the baseline temperature was increased to 42°C and the peak temperature reduced. These findings suggest that 2 mechanisms underlie the improved acquisition of CHEPs: increased synchronization of afferent volley, yielding larger-amplitude evoked potentials in response to the same rating of intensity; and reduced inter-trial variability.

WS3.3. The Values of H-Reflex and Other Late Responses in Disease

It is relatively easy to record the H reflex from soleus, and many authorities still teach that it can be obtained only from this muscle. Inability to record the soleus H reflex has three possible causes: (i) poor technique; (ii) low central excitability; (iii) loss of afferent fibres due to, e.g., peripheral neuropathy or nerve root pathology. If the reason is (ii), all reflexes, in upper and lower limbs, will be difficult to elicit, and the reflex response should then become apparent during a steady voluntary contraction. A voluntary contraction not only potentiates the reflex but it also decreases the stimulus intensity needed for the reflex, ensures that the reflex involves the contracting muscle, and greatly reduces the attenuation of the response that occurs with higher stimulus rates. It reduces the latency of the reflex responses only slightly (<0.5 ms). During a steady voluntary contraction of the test muscle, H reflexes can be recorded for most limb muscles, and provide information about conduction across the most relevant spinal segments (e.g., C5/6, C6, C6/7, C8/T1, L3/4, L4/5 and S1). In routine diagnostic practice, I assess reflex conduction in perhaps 60% of patients because this provides insight into conduction in afferent and efferent axons over the entire peripheral nerve pathway. In diagnostic practice we focus on pathology that causes loss of reflex function. However, if you can record H reflexes at rest from muscles that normally have no H reflex unless they are contracting voluntarily, there is presumptive evidence of hyperreflexia. If there is EMG evidence of denervation in that muscle, this suggests UMN and LMN changes for a single muscle, and this is support for a diagnosis of motor neurone disease. F waves can provide complementary information about motor axons because the H reflex preferentially involves slowly conduction motor axons from small low-threshold motoneurones, but the F wave measures conduction in larger axons that are not discharged reflexly by the intense afferent volley produced by the supramaximal stimulus.

Crosstalk opposing view: Independent fusimotor control of muscle spindles in humans: there is little to gain.

Crosstalk opposing view: Independent fusimotor control of muscle spindles in humans: there is little to gain.

Fully Implantable Plantar Cutaneous Augmentation System for Rats Using Closed-loop Electrical Nerve Stimulation.

Plantar cutaneous feedback plays an important role in stable and efficient gait, by modulating the activity of ankle dorsi- and plantar-flexor muscles. However, central and peripheral nervous system trauma often decrease plantar cutaneous feedback and/or interneuronal excitability in processing the plantar cutaneous feedback. In this study, we tested a fully implantable neural recording and stimulation system augmenting plantar cutaneous feedback. Electromyograms were recorded from the medial gastrocnemius muscle for stance phase detection, while biphasic stimulation pulses were applied to the distal-tibial nerve during the stance phase to augment plantar cutaneous feedback. A Bluetooth low energy and a Qi-standard inductive link were adopted for wireless communication and wireless charging, respectively. To test the operation of the system, one intact rat walked on a treadmill with the electrical system implanted into its back. Leg kinematics were recorded to identify the stance phase. Stimulation was applied, with a 250-ms onset delay from stance onset and 200-ms duration, resulting in the onset at 47.58±2.82% of stance phase and the offset at 83.49±4.26% of stance phase (Mean±SEM). The conduction velocity of the compound action potential (31.2 m/s and 41.6 m/s at 1·T and 2·T, respectively) suggests that the evoked action potential was characteristic of an afferent volley for cutaneous feedback. We also demonstrated successful wireless charging and system reset functions. The experimental results suggest that the presented implantable system can be a valuable neural interface tool to investigate the effect of plantar cutaneous augmentation on gait in a rat model.

Variations in Muscle Activity and Exerted Torque During Temporary Blood Flow Restriction in Healthy Individuals.

Recent studies suggest that transitory blood flow restriction (BFR) may improve the outcomes of training from anatomical (hypertrophy) and neural control perspectives. Whilst the chronic consequences of BFR on local metabolism and tissue adaptation have been extensively investigated, its acute effects on motor control are not yet fully understood. In this study, we compared the neuromechanical effects of continuous BFR against non-restricted circulation (atmospheric pressure—AP), during isometric elbow flexions. BFR was achieved applying external pressure either between systolic and diastolic (lower pressure—LP) or 1.3 times the systolic pressure (higher pressure—HP). Three levels of torque (15, 30, and 50% of the maximal voluntary contraction—MVC) were combined with the three levels of pressure for a total of 9 (randomized) test cases. Each condition was repeated 3 times. The protocol was administered to 12 healthy young adults. Neuromechanical measurements (torque and high-density electromyography—HDEMG) and reported discomfort were used to investigate the response of the central nervous system to BFR. The investigated variables were: root mean square (RMS), and area under the curve in the frequency domain—for the torque, and average RMS, median frequency and average muscle fibres conduction velocity—for the EMG. The discomfort caused by BFR was exacerbated by the level of torque and accumulated over time. The torque RMS value did not change across conditions and repetitions. Its spectral content, however, revealed a decrease in power at the tremor band (alpha-band, 5–15 Hz) which was enhanced by the level of pressure and the repetition number. The EMG amplitude showed no differences whilst the median frequency and the conduction velocity decreased over time and across trials, but only for the highest levels of torque and pressure. Taken together, our results show strong yet transitory effects of BFR that are compatible with a motor neuron pool inhibition caused by increased activity of type III and IV afferences, and a decreased activity of spindle afferents. We speculate that a compensation of the central drive may be necessary to maintain the mechanical output unchanged, despite disturbances in the afferent volley to the motor neuron pool.

Intensity and Dose of Neuromuscular Electrical Stimulation Influence Sensorimotor Cortical Excitability.

Neuromuscular electrical stimulation (NMES) of the nervous system has been extensively used in neurorehabilitation due to its capacity to engage the muscle fibers, improving muscle tone, and the neural pathways, sending afferent volleys toward the brain. Although different neuroimaging tools suggested the capability of NMES to regulate the excitability of sensorimotor cortex and corticospinal circuits, how the intensity and dose of NMES can neuromodulate the brain oscillatory activity measured with electroencephalography (EEG) is still unknown to date. We quantified the effect of NMES parameters on brain oscillatory activity of 12 healthy participants who underwent stimulation of wrist extensors during rest. Three different NMES intensities were included, two below and one above the individual motor threshold, fixing the stimulation frequency to 35 Hz and the pulse width to 300 μs. Firstly, we efficiently removed stimulation artifacts from the EEG recordings. Secondly, we analyzed the effect of amplitude and dose on the sensorimotor oscillatory activity. On the one hand, we observed a significant NMES intensity-dependent modulation of brain activity, demonstrating the direct effect of afferent receptor recruitment. On the other hand, we described a significant NMES intensity-dependent dose-effect on sensorimotor activity modulation over time, with below-motor-threshold intensities causing cortical inhibition and above-motor-threshold intensities causing cortical facilitation. Our results highlight the relevance of intensity and dose of NMES, and show that these parameters can influence the recruitment of the sensorimotor pathways from the muscle to the brain, which should be carefully considered for the design of novel neuromodulation interventions based on NMES.

Evidence of two modes of spiking evoked in human firing motoneurones by Ia afferent electrical stimulation.

Neurone firing behaviour is a result of complex interaction between synaptic inputs and cellular intrinsic properties. Intriguing firing behaviour, delayed spiking, was shown in some neurones, in particular, in cat neocortical neurones and rat pyramidal hippocampal neurones. In contrast, the similar spiking mode was not reported for animal spinal motoneurones. In the present study, an attempt was made to look for possible evidence of delayed spiking in human motoneurones firing within the low-frequency, sub-primary range, characteristic for voluntary muscle contractions and postural tasks. Forty-seven firing motor units (MUs) were analyzed in ten experiments on three muscles (the flexor carpi ulnaris, the tibialis anterior, and the abductor pollicis brevis) in four healthy humans. Single MUs were activated by gentle voluntary muscle contractions. MU peri-stimulus time histograms, durations of inter-spike intervals, and motoneurone excitability changes within a target interspike interval were analyzed. It was found that during testing the firing motoneurone excitability by small, transient excitatory Ia afferent volley, depending firstly on volley timing within a target interspike interval and excitatory volley strength, the same motoneurone displayed either the direct short-latency response (the H-reflex) or the delayed response (with prolonged and variable latency). Thus, the findings, for the first time, provide evidence for a possibility of two modes of spiking in firing motoneurones. Methods of the estimation of delayed responses and their possible functional significance are discussed. It is emphasized that, for understanding of this issue, the integration of data from studies on experimental animals and humans is desirable.

Aspects of cortical area responsibilities while learning a visually cued spatiotemporal motor task.

Aspects of cortical area responsibilities while learning a visually cued spatiotemporal motor task.

Beta Rebound as an Index of Temporal Integration of Somatosensory and Motor Signals.

Modulation of cortical beta rhythm (15–30 Hz) is present during preparation for and execution of voluntary movements as well as during somatosensory stimulation. A rebound in beta synchronization is observed after the end of voluntary movements as well as after somatosensory stimulation and is believed to describe the return to baseline of sensorimotor networks. However, the contribution of efferent and afferent signals to the beta rebound remains poorly understood. Here, we applied electrical median nerve stimulation (MNS) to the right side followed by transcranial magnetic stimulation (TMS) on the left primary motor cortex after either 15 or 25 ms. Because the afferent volley reaches the somatosensory cortex after about 20 ms, TMS on the motor cortex was either anticipating or following the cortical arrival of the peripheral stimulus. We show modulations in different beta sub-bands and in both hemispheres, following a pattern of greater resynchronization when motor signals are paired with a peripheral one. The beta rebound in the left hemisphere (stimulated) is modulated in its lower frequency range when TMS precedes the cortical arrival of the afferent volley. In the right hemisphere (unstimulated), instead, the increase is limited to higher beta frequencies when TMS is delivered after the arrival of the afferent signal. In general, we demonstrate that the temporal integration of afferent and efferent signals plays a key role in the genesis of the beta rebound and that these signals may be carried in parallel by different beta sub-bands.

Distinct Age-Dependent C Fiber-Driven Oscillatory Activity in the Rat Somatosensory Cortex.

When skin afferents are activated, the sensory signals are transmitted to the spinal cord and eventually reach the primary somatosensory cortex (S1), initiating the encoding of the sensory percept in the brain. While subsets of primary afferents mediate specific somatosensory information from an early age, the subcortical pathways that transmit this information undergo striking changes over the first weeks of life, reflected in the gradual emergence of specific sensory behaviors. We therefore hypothesized that this period is associated with differential changes in the encoding of incoming afferent volleys in S1. To test this, we compared S1 responses to A fiber skin afferent stimulation and A + C skin afferent fiber stimulation in lightly anaesthetized male rats at postnatal day (P)7, P14, P21, and P30. Differences in S1 activity following A and A + C fiber stimulation changed dramatically over this period. At P30, A + C fiber stimulation evoked significantly larger γ, β, and α energy increases compared with A fiber stimulation alone. At younger ages, the changes in S1 oscillatory activity evoked by the two afferent volleys were not significantly different. Silencing TRPV1+ C fibers with QX-314 significantly reduced the γ and β S1 oscillatory energy increases evoked by A + C fibers, at P30 and P21, but not at younger ages. Thus, C fibers differentially modulate S1 oscillatory activity only from the third postnatal week, well after the functional maturation of the somatosensory cortex. This age-related change in afferent evoked S1 oscillatory activity may underpin the maturation of sensory discrimination in the developing brain.

Corticospinal excitability modulation by pairing peripheral nerve stimulation with cortical states of movement initiation.

We compare the effects on corticospinal excitability of repeatedly delivering peripheral nerve stimulation at three time points (-30ms, 0ms, +50ms) relative to muscle onset in a cue-guided task. Plastic changes in excitability are only observed when stimuli are delivered immediately before the time when muscles activate, while stimuli delivered at muscle onset or shortly later (0, +50ms) have no effect. Plastic effects are abolished if there is ongoing volitional electromyogram activity in the muscles prior to the onset of the phasic contraction. The plastic effects induced by timing peripheral stimulation relative to electromyographic markers of muscle activation are as effective as those that occur if stimulation is timed relative to electroencephalographic markers of motor cortical activation. We provide a simple alternative protocol to induce plasticity in people in whom electroencephalogram recording is difficult. Plastic changes in corticospinal excitability (CSE) and motor function can be induced in a targeted and long-term manner if afferent volleys evoked by peripheral nerve stimulation are repeatedly associated with the peak of premovement brain activity assessed with an electroencephalogram (EEG). The present study investigated whether other factors might also characterize this optimal brain state for plasticity induction. In healthy human volunteers (n=24), we found that the same reliable changes in CSE can be induced by timing peripheral afferent stimulation relative to the onset of electromyogram (EMG) activity rather than using the EEG peak. Specifically, we observed an increase in CSE when peripheral stimulation activated the cortex just before movement initiation. By contrast, there was no effect on CSE if the afferent input reached the cortex at the same time or after EMG onset, consistent with the idea that the temporal order of synaptic activation from afferent input and voluntary movement is important for production of plasticity. Finally, in 14 volunteers, we found that background voluntary muscle activity prior to movement also abolished the effect on CSE. One possible explanation is that the intervention strengthens synapses that are inactive at rest but change their activity in anticipation of movement, and that the intervention fails when the synapses are tonically active during background EMG activity. Overall, we demonstrate that, in individuals with voluntary control of muscles targeted by our intervention, EMG signals are a suitable alternative to an EEG for inducing plasticity by coupling movement-related brain states with peripheral afferent input.

Transcutaneous Auricular Vagus Nerve Stimulation.

Invasive vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. Besides recognized clinical efficacy in about 60% of patients, there are major drawbacks such as invasiveness and common side effects including hoarseness, sore throat, shortness of breath, and coughing. Invasive VNS applies electrical stimulation to the left cervical branch of the vagus nerve and excites thick-myelinated afferent nerve fibers. Peripheral vagus nerve afferent volley initiates brainstem activity in the nucleus of the solitary tract and provokes typical brainstem and cerebral activation patterns that mediate the anticonvulsive mode of action. Whereas invasive VNS is an established neuromodulatory treatment in drug-resistant epilepsy, transcutaneous VNS (tVNS) of the auricular branch of the vagus nerve is suggested to be an alternative access path to the same neuronal network without invasiveness. Preclinical and clinical studies indicate that especially the cymba conchae of the auricle is selectively supplied by the auricular branch of the vagus nerve. Recent anatomical data demonstrate existence and quantity of thick-myelinated afferent nerve fibers of the left auricular branch of the vagus nerve that carries 21% of thick-myelinated afferent nerve fibers counted in the left thoracic vagus nerve in humans. Projection of auricular branch of the vagus nerve afferents from the auricle to the nucleus of the solitary tract is known from histochemical and electrophysiological experiments in rodents and confirmed in humans by functional imaging. Cerebral activation patterns triggered by invasive and tVNS resemble each other in appearance. Clinical trials in patients address safety and performance of tVNS and provide evidence for application in drug-resistant epilepsy.

Optogenetic recruitment of spinal reflex pathways from large-diameter primary afferents in non-transgenic rats transduced with AAV9/Channelrhodopsin 2.

Key points We demonstrated optical activation of primary somatosensory afferents with high selectivity to fast‐conducting fibres by means of adeno‐associated virus 9 (AAV9)‐mediated gene transduction in dorsal root ganglion (DRG) neurons.AVV9 expressing green fluorescent protein showed high selectivity and transduction efficiency for fast‐conducting, large‐sized DRG neurons.Compared with conventional electrical stimulation, optically elicited volleys in primary afferents had higher sensitivity with stimulus amplitude, but lower sensitivity with stimulus frequency.Optically elicited dorsal root volleys activated postsynaptic neurons in the segmental spinal pathway.This proposed technique will help establish the causal relationships between somatosensory afferent inputs and neural responses in the CNS as well as behavioural outcomes in higher mammals where transgenic animals are not available. Previously, fundamental structures and their mode of action in the spinal reflex circuit were determined by confirming their input–output relationship using electrophysiological techniques. In those experiments, the electrical stimulation of afferent fibres was used as a core element to identify different types of reflex pathways; however, a major disadvantage of this technique is its non‐selectivity. In this study, we investigated the selective activation of large‐diameter afferents by optogenetics combined with a virus vector transduction technique (injection via the sciatic nerve) in non‐transgenic male Jcl:Wistar rats. We found that green fluorescent protein gene transduction of rat dorsal root ganglion (DRG) neurons with a preference for medium‐to‐large‐sized cells was achieved using the adeno‐associated virus 9 (AAV9) vector compared with the AAV6 vector (P = 0.021). Furthermore, the optical stimulation of Channelrhodopsin 2 (ChR2)‐expressing DRG neurons (transduced by AAV9) produced compound action potentials in afferent nerves originating from fast‐conducting nerve fibres. We also confirmed that physiological responses to different stimulus amplitudes were comparable between optogenetic and electrophysiological activation. However, compared with electrically elicited responses, the optically elicited responses had lower sensitivity with stimulus frequency. Finally, we showed that afferent volleys evoked by optical stimulation were sufficient to activate postsynaptic neurons in the spinal reflex arc. These results provide new ways for understanding the role of sensory afferent input to the central nervous system regarding behavioural control, especially when genetically manipulated animals are not available, such as higher mammals including non‐human primates.

P69-S Cutaneous silent period behavior in different motor neuron diseases phenotypes

Background The cutaneous silent period (CSP) corresponds to a reduced electric activity of a contracting muscle, after electrical stimulation of sensory fibers. The afferent volley causes a presynaptic inhibition of spinal motor neurons (LMN) modulated by complex spinal circuits. CSP behavior in different motor neuron diseases (MND) phenotypes is unknown. Materials and methods We included 20 MND patients and 15 controls. CSP was obtained by applying electrical stimulation of the 5th finger. Surface EMG recordings were obtained from ADM muscle. CSP duration was defined by the time between a drop of rectified averaged EMG below 80%, and the final return above 80%, of baseline EMG. The mean duration was obtained from 10 consecutive curves obtained before and during co-contraction of the contralateral ADM muscle. Results MND patients had a median age of 59 years. 12 were diagnosed as amyotrophic lateral sclerosis (ALS), 6 as progressive muscular atrophy (PMA), 2 as primary lateral sclerosis (PLS). Median CSP duration was similar between controls and patients. During contralateral ADM contraction, CSP duration did not change in controls, patients with ALS and PMA, but decreased by 28% in PLS patients. Conclusions We present preliminary results suggesting that CSP behavior is not homogenous in different phenotypes of MND. We previously observed that reflex contralateral activation of the homonymous contralateral hand muscles is frequent in patients with PLS, indicating spinal cord hyperexcitability. Our CSP results suggest that this method can contribute to dissect the mechanisms underlying abnormal LMN excitability in patients with corticospinal tract lesion.