Evaluation of mechanomyogram efficacy as a tool for assessing paired-pulse inhibition of blink reflex early R1 component.

INTRODUCTION/AIMS: Paired-pulse stimulation provides clinically useful information regarding sensory inhibition. When supraorbital nerve stimulation is repeated within a short interval, the response to the second stimulation is reduced to varying degrees. This magnitude of change in stimulation response can be monitored by electromyogram (EMG) or by mechanomyogram (MMG) as in this report. MMG has some advantages such as being less time consuming and lacking stimulus artifact. We compared the use of MMG and EMG to validate MMG as an effective method of assessing blink reflex paired-pulse inhibition. METHODS: Eight volunteers participated. Participants received electrical stimulation to the supraorbital nerve of each side. A paired-pulse paradigm was employed, varying the conditioning-test interval between 5 and 800 ms. The R1 component of the induced blink reflex was simultaneously recorded by EMG using a pair of electrodes placed on the lower eyelid and by MMG using an accelerometer placed between the electrodes. RESULTS: The correlation coefficient of the R1 amplitude between MMG and EMG of the grand-averaged waveforms was 0.99. The average participant r value was .91 (range .76-.99). Similar analyses were performed for the amplitude variation of the second response relative to the first response. Results correlated well, yielding r values of .97 and .86 for the grand-averaged waveform and the average for each subject. DISCUSSION: The present results demonstrate that MMG could be an alternative to EMG in assessing paired-pulse inhibition of the electrical blink reflex R1 component.

Short-latency prepulse inhibition of the trigeminal blink reflex.

Prepulse inhibition (PPI) is a well-established phenomenon wherein a weak sensory stimulus attenuates the startle reflex triggered by a subsequent strong stimulus. Within the circuit, variations in target responses observed for PPI paradigms represent prepulse-induced excitability changes. However, little is known about the mechanism of PPI. Here, we focused on short-latency PPI of the trigeminal blink reflex R1 signal with an oligosynaptic reflex arc through the principal sensory trigeminal nucleus and the facial nucleus. As the facial nucleus is facilitatory to any input, R1 PPI is the phenomenon in the former nucleus. Considering that GABAergic modulation may be involved in PPI, this study investigated whether the PPI mechanism includes GABA-A equivalent inhibition, which peaks at approximately 30 ms in humans. In 12 healthy volunteers, the reflex was elicited by electrical stimulation of the supraorbital nerve, and recorded at the ipsilateral lower eyelid by accelerometer. Stimulus intensity was 1.5 times the R1 threshold for test stimulus and 0.9 times for the prepulse. The prepulse-test interval (PTI) was 5-150 ms. Results showed significant inhibition at 40-and 80-150-ms PTIs but not at 20-, 30-, 50-, 60-, and 70-ms PTIs, yielding two distinct inhibitions of different time scales. This corresponds well to the early and late components of inhibitory post synaptic potentials by GABA-A and GABA-B receptor activation. Thus, the data support the contribution of inhibitory post synaptic potentials elicited by the prepulse to the observed PPI. As inhibitory function-related diseases may impair the different inhibition components to varying degrees, methods deconvoluting each inhibitory component contribution are of clinical importance.

Age and sex effects on paired-pulse suppression and prepulse inhibition of auditory evoked potentials.

Responses to a sensory stimulus are inhibited by a preceding stimulus; if the two stimuli are identical, paired-pulse suppression (PPS) occurs; if the preceding stimulus is too weak to reliably elicit the target response, prepulse inhibition (PPI) occurs. PPS and PPI represent excitability changes in neural circuits induced by the first stimulus, but involve different mechanisms and are impaired in different diseases, e.g., impaired PPS in schizophrenia and Alzheimer's disease and impaired PPI in schizophrenia and movement disorders. Therefore, these measures provide information on several inhibitory mechanisms that may have roles in clinical conditions. In the present study, PPS and PPI of the auditory change-related cortical response were examined to establish normative data on healthy subjects (35 females and 32 males, aged 19-70 years). We also investigated the effects of age and sex on PPS and PPI to clarify whether these variables need to be considered as biases. The test response was elicited by an abrupt increase in sound pressure in a continuous sound and was recorded by electroencephalography. In the PPS experiment, the two change stimuli to elicit the cortical response were a 15-dB increase from the background of 65 dB separated by 600 ms. In the PPI experiment, the prepulse and test stimuli were 2- and 10-dB increases, respectively, with an interval of 50 ms. The results obtained showed that sex exerted similar effects on the two measures, with females having stronger test responses and weaker inhibition. On the other hand, age exerted different effects: aging correlated with stronger test responses and weaker inhibition in the PPS experiment, but had no effects in the PPI experiment. The present results suggest age and sex biases in addition to normative data on PPS and PPI of auditory change-related potentials. PPS and PPI, as well as other similar paradigms, such as P50 gating, may have different and common mechanisms. Collectively, they may provide insights into the pathophysiologies of diseases with impaired inhibitory function.

The 40-Hz auditory steady-state response enhanced by beta-band subharmonics.

The 40-Hz auditory steady-state response (ASSR) has received special attention as an index of gamma oscillations owing to its association with various neuropsychiatric disorders including schizophrenia. When a periodic stimulus is presented, oscillatory responses are often elicited not only at the stimulus frequency, but also at its harmonic frequencies. However, little is known about the effect of 40-Hz subharmonic stimuli on the activity of the 40-Hz ASSR. In the present magnetoencephalography study, we focused on the nature of oscillation harmonics and examined oscillations in a wide frequency range using a time-frequency analysis during the 6.67-, 8-, 10-, 13.3-, 20-, and 40-Hz auditory stimuli in 23 healthy subjects. The results suggested that the 40-Hz ASSR represents activation of a specific circuit tuned to this frequency. Particularly, oscillations elicited by 13.3- and 20-Hz stimuli exhibited significant enhancement at 40 Hz without changing those at the stimulus frequency. In addition, it was found that there was a non-linear response to stimulation in the beta band. We also demonstrated that the inhibition of beta to low-gamma oscillations by the 40-Hz circuit contributed to the violation of the rule that harmonic oscillations gradually decrease at higher frequencies. These findings can advance our understanding of oscillatory abnormalities in patients with schizophrenia in the future.

Brain-wide network analysis of resting-state neuromagnetic data.

The present study performed a brain-wide network analysis of resting-state magnetoencephalograms recorded from 53 healthy participants to visualize elaborate brain maps of phase- and amplitude-derived graph-theory metrics at different frequencies. To achieve this, we conducted a vertex-wise computation of threshold-independent graph metrics by combining proportional thresholding and a conjunction analysis and applied them to a correlation analysis of age and brain networks. Source power showed a frequency-dependent cortical distribution. Threshold-independent graph metrics derived from phase- and amplitude-based connectivity showed similar or different distributions depending on frequency. Vertex-wise age-brain correlation maps revealed that source power at the beta band and the amplitude-based degree at the alpha band changed with age in local regions. The present results indicate that a brain-wide analysis of neuromagnetic data has the potential to reveal neurophysiological network features in the human brain in a resting state.

Cortical activity during the wind-up of flexion reflex and pain: a magnetoencephalographic study using time-frequency analysis.

Wind-up is a nociceptive-specific phenomenon in which pain sensations are facilitated, in a frequency-dependent manner, by the repeated application of noxious stimuli of constant intensity, with invariant tactile sensations. Thus, cortical activities during wind-up could be an alteration associated with pain potentiation. We aimed to investigate somatosensory-evoked cortical responses and induced brain oscillations during wind-up by recording magnetoencephalograms. Wind-up was produced by the application of 11 consecutive electrical stimuli to the sural nerve, repeated at a frequency of 1 Hz without varying the intensity. The augmentation of flexion reflexes and pain rating scores were measured simultaneously as an index of wind-up. In the time-frequency analyses, the γ-band late event-related synchronization and the ß-band event-related desynchronization were observed in the primary somatosensory region and the bilateral operculo-insular region, respectively. Repetitive exposure to the stimuli enhanced these activities, along with an increase in the flexion reflex magnitude. The evoked cortical activity reflected novelty, with no alteration to these repetitive stimuli. Observed oscillations enhanced by repetitive stimulation at a constant intensity could reflect a pain mechanism associated with wind-up.

Mechanisms of Short- and Long-Latency Sensory Suppression: Magnetoencephalography Study.

Prepulse inhibition (PPI) is sensory suppression whose mechanism (i.e., whether PPI originates from specific inhibitory mechanisms) remains unclear. In this study, we applied the combination of short-latency PPI and long-latency paired pulse suppression in 17 healthy subjects using magnetoencephalography to investigate the mechanisms of sensory suppression. Repeats of a 25-ms pure tone without a blank at 800 Hz and 70 dB were used for a total duration of 1600 ms. To elicit change-related cortical responses, the sound pressure of two consecutive tones in this series at 1300 ms was increased to 80 dB (Test). For the conditioning stimuli, the sound pressure was increased to 73 dB at 1250 ms (Pre 1) and 80 dB at 700 ms (Pre 2). Six stimuli were randomly presented as follows: (1) Test alone, (2) Pre 1 alone, (3) Pre 1 + Test, (4) Pre 2 + Test, (5) Pre 2 + Pre 1, and (6) Pre 2 + Pre 1 + Test. The inhibitory effects of the conditioning stimuli were evaluated using N100m/P200m components. The results showed that both Pre 1 and Pre 2 significantly suppressed the Test response. Moreover, the inhibitory effects of Pre 1 and Pre 2 were additive. However, when both prepulses were present, Pre 2 significantly suppressed the Pre 1 response, suggesting that the Pre 1 response amplitude was not a determining factor for the degree of suppression. These results suggested that the suppression originated from a specific inhibitory circuit independent of the excitatory pathway.

Target Site of Prepulse Inhibition of the Trigeminal Blink Reflex in Humans.

Despite the clinical significance of prepulse inhibition (PPI), the mechanisms are not well understood. Herein, we present our investigation of PPI in the R1 component of electrically induced blink reflexes. The effect of a prepulse was explored with varying prepulse test intervals (PTIs) of 20-600 ms in 4 females and 12 males. Prepulse-test combinations included the following: stimulation of the supraorbital nerve (SON)-SON [Experiment (Exp) 1], sound-sound (Exp 2), the axon of the facial nerve-SON (Exp 3), sound-SON (Exp 4), and SON-SON with a long trial-trial interval (Exp 5). Results showed that (1) leading weak SON stimulation reduced SON-induced ipsilateral R1 with a maximum effect at a PTI of 140 ms, (2) the sound-sound paradigm resulted in a U-shaped inhibition time course of the auditory startle reflex (ASR) peaking at 140 ms PTI, (3) facial nerve stimulation showed only a weak effect on R1, (4) a weak sound prepulse facilitated R1 but strongly inhibited SON-induced late blink reflexes (LateRs) with a similar U-shaped curve, and (5) LateR in Exp 5 was almost completely absent at PTIs >80 ms. These results indicate that the principal sensory nucleus is responsible for R1 PPI. Inhibition of ASR or LateR occurs at a point in the startle reflex circuit where auditory and somatosensory signals converge. Although the two inhibitions are different in location, their similar time courses suggest similar neural mechanisms. As R1 has a simple circuit and is stable, R1 PPI helps to clarify PPI mechanisms.SIGNIFICANCE STATEMENT Prepulse inhibition (PPI) is a phenomenon in which the startle response induced by a startle stimulus is suppressed by a preceding nonstartle stimulus. This study demonstrated that the R1 component of the trigeminal blink reflex shows clear PPI despite R1 generation within a circuit consisting of the trigeminal and facial nuclei, without startle reflex circuit involvement. Thus, PPI is not specific to the startle reflex. In addition, PPI of R1, the auditory startle reflex, and the trigeminal late blink reflex showed similar time courses in response to the prepulse test interval, suggesting similar mechanisms regardless of inhibition site. R1 PPI, in conjunction with other paradigms with different prepulse-test combinations, would increase understanding of the underlying mechanisms.

Relationship of loudness-dependent auditory evoked potentials with change-related cortical responses.

Previous studies have suggested that change-related cortical responses are phenomena similar to the onset response and could be applied to the loudness dependence of auditory evoked potential (LDAEP) paradigm. In the present study, we examined the relationship between LDAEP and the change-related response using electroencephalography findings in 50 healthy subjects. There were five conditions (55, 65, 75, 85, and 95 dB) for LDAEP and five similar conditions (abrupt sound pressure increase from 70 to 75, 80, 85, 90, and 95 dB) for the change-related response. Both the onset and abrupt sound pressure increase evoked a triphasic response with peaks at approximately 50 (P50), 100 (N100), and 200 (P200) ms. We calculated the peak-to-peak amplitudes for P50/N100 and N100/P200. Medians and slopes for P50/N100 and N100/P200 amplitudes were calculated and compared between the two measures. Results revealed a significant correlation for both the slope and median for P50/N100 (r = 0.36, 0.37, p = 1.0 × 10-2, 7.9 × 10-3), N100/P200 (r = 0.40, 0.34, p = 4.0 × 10-3, 1.6 × 10-2), and P50/N100/P200 (r = 0.36, 0.35, p = 1.0 × 10-2, 1.3 × 10-2). These results suggested that the change-related response and LDAEP shared generation mechanisms at least partially.

Catechol-O-methyltransferase (COMT) Val158Met Polymorphism and Prepulse Inhibition of the Change-related Cerebral Response.

Change-related potentials elicited by an abrupt sound feature's change are attenuated by a leading weak sound (prepulse inhibition: PPI). We investigated whether the PPI index is associated with the catechol-methyltransferase (COMT) Val158Met polymorphism (rs4680), which is involved in the metabolism of dopamine in the prefrontal cortex. Healthy subjects with normal hearing were recruited (n = 70). A train of 100-Hz clicks 650 ms in duration was used. The test stimulus was an abrupt increase in sound intensity (+10 dB) from the baseline (70 dB) provided at 400 ms after the sound onset. Three consecutive clicks at 30, 40, and 50 ms before the change's onset were greater (+3 or +5 dB) from the baseline as a prepulse. The targeting auditory evoked potential component was Change-N1 peaking approx. 130 ms after the change onset. We calculated the inhibition level as the% inhibition of the Change-N1 amplitude by a prepulse. The %PPI in the Met-carriers was significantly greater than that in the Val/Val-individuals. Our results suggest that dopamine might play a role in the PPI of the change-related response. We propose that this index has the potential to identify an intermediate phenotype in psychiatric disorders such as schizophrenia.

A Minimally Invasive Method for Observing Wind-Up of Flexion Reflex in Humans: Comparison of Electrical and Magnetic Stimulation.

Wind-up like pain or temporal summation of pain is a phenomenon in which pain sensation is increased in a frequency-dependent manner by applying repeated noxious stimuli of uniform intensity. Temporal summation in humans has been studied by observing the increase in pain or flexion reflex by repetitive electrical or thermal stimulations. Nonetheless, because the measurement is accompanied by severe pain, a minimally invasive method is desirable. Gradual augmentation of flexion reflex and pain induced by repetitive stimulation of the sural nerve was observed using three stimulation methods-namely, bipolar electrical, magnetic, and monopolar electrical stimulation, with 11 healthy male subjects in each group. The effects of frequency, intensity, and number of repetitive stimuli on the increase in the magnitude of flexion reflex and pain rating were compared among the three methods. The reflex was measured using electromyography (EMG) from the short head of the biceps femoris. All three methods produced a frequency- and intensity-dependent progressive increase in reflex and pain; pain scores were significantly lower for magnetic and monopolar stimulations than for bipolar stimulation (P < 0.05). The slope of increase in the reflex was steep during the first 4-6 stimuli but became gentler thereafter. In the initial phase, an increase in the reflex during the time before signals of C-fibers arrived at the spinal cord was observed in experiments using high-frequency stimulation, suggesting that wind-up was caused by inputs of A-fibers without the involvement of C-fibers. Magnetic and monopolar stimulations are minimally invasive and useful methods for observing the wind-up of the flexion reflex in humans. Monopolar stimulation is convenient because it does not require special equipment. There is at least a partial mechanism underlying the wind-up of the flexion reflex that does not require C-fibers.

Review of techniques useful for the assessment of sensory small fiber neuropathies: Report from an IFCN expert group.

Nerve conduction studies (NCS) are an essential aspect of the assessment of patients with peripheral neuropathies. However, conventional NCS do not reflect activation of small afferent fibers, including Aδ and C fibers. A definitive gold standard for laboratory evaluation of these fibers is still needed and therefore, clinical evaluation remains fundamental in patients with small fiber neuropathies (SFN). Several clinical and research techniques have been developed for the assessment of small fiber function, such as (i) microneurography, (ii) laser evoked potentials, (iii) contact heat evoked potentials, (iv) pain-related electrically evoked potentials, (v) quantitative thermal sensory testing, (vi) skin biopsy-intraepidermal nerve fiber density and (vii) corneal confocal microscopy. The first five are physiological techniques, while the last two are morphological. They all have advantages and limitations, but the combined use of an appropriate selection of each of them would lead to gathering invaluable information for the diagnosis of SFN. In this review, we present an update on techniques available for the study of small afferent fibers and their clinical applicability. A summary of the anatomy and important physiological aspects of these pathways, and the clinical manifestations of their dysfunction is also included, in order to have a minimal common background.

Neural Sources of Vagus Nerve Stimulation-Induced Slow Cortical Potentials.

OBJECTIVES: This study investigated neuronal sources of slow cortical potentials (SCPs) evoked during vagus nerve stimulation (VNS) in patients with epilepsy who underwent routine electroencephalography (EEG) after implantation of the device. MATERIALS AND METHODS: We analyzed routine clinical EEG from 24 patients. There were 5 to 26 trains of VNS during EEG. To extract SCPs from the EEG, a high-frequency filter of 0.2 Hz was applied. These EEG epochs were averaged and used for source analyses. The averaged waveforms for each patient and their grand average were subjected to multidipole analysis. Patients with at least 50% seizure frequency reduction were considered responders. Findings from EEG analysis dipole were compared with VNS responses. RESULTS: VNS-induced focal SCPs whose dipoles were estimated to be located in several cortical areas including the medial prefrontal cortex, postcentral gyrus, and insula, with a significantly higher frequency in patients with a good VNS response than in those with a poor response. CONCLUSIONS: This study suggested that some VNS-induced SCPs originating from the so-called vagus afferent network are related to the suppression of epileptic seizures.

Mechanisms of Long-Latency Paired Pulse Suppression: MEG Study.

Paired pulse suppression is an electrophysiological method used to evaluate sensory suppression and often applied to patients with psychiatric disorders. However, it remains unclear whether the suppression comes from specific inhibitory mechanisms, refractoriness, or fatigue. In the present study, to investigate mechanisms of suppression induced by an auditory paired pulse paradigm in 19 healthy subjects, magnetoencephalography was employed. The control stimulus was a train of 25-ms pure tones of 65 dB SPL for 2500 ms. In order to evoke a test response, the sound pressure of two consecutive tones at 2200 ms in the control sound was increased to 80 dB (Test stimulus). Similar sound pressure changes were also inserted at 1000 (CS2) and 1600 (CS1) ms as conditioning stimuli. Four stimulus conditions were used; (1) Test alone, (2) Test + CS1, (3) Test + CS1 + CS2, and (4) Test + CS2, with the four sound stimuli randomly presented and cortical responses averaged at least 100 times for each condition. The baseline-to-peak and peak-to-peak amplitudes of the P50m, N100m, and P200m components of the test response were compared among the four conditions. In addition, the response to CS1 was compared between conditions (2) and (3). The results showed significant test response suppression by CS1. While the response to CS1 was significantly suppressed when CS2 was present, it did not affect suppression of the test response by CS1. It was thus suggested that the amplitude of the response to a conditioning stimulus is not a factor to determine the inhibitory effects of the test response, indicating that suppression is due to an external influence on the excitatory pathway.

Suppression of Low-Frequency Gamma Oscillations by Activation of 40-Hz Oscillation.

Gamma oscillations have received considerable attention owing to their association with cognitive function and various neuropsychiatric disorders. However, interactions of gamma oscillations at different frequency bands in humans remain unclear. In the present magnetoencephalographic study, brain oscillations in a wide frequency range were examined using a time-frequency analysis during the 20-, 30-, 40-, and 50-Hz auditory stimuli in 21 healthy subjects. First, dipoles for auditory steady-state response (ASSR) were estimated and interaction among oscillations at 10-60 Hz was examined using the source strength waveforms. Results showed the suppression of ongoing low-gamma oscillations at approximately 30 Hz during stimulation at 40 Hz. Second, multi-dipole analyses suggested that the main dipole for ASSR and dipoles for suppressed low-frequency gamma oscillations were distinct. Third, an all-sensor analysis was performed to clarify the distribution of the 40-Hz ASSR and suppression of low-frequency gamma oscillations. Notably, the area of suppression surrounded the center of the 40-Hz ASSR and showed a trend of extending to the vertex, indicating that different groups of neurons were responsible for these two gamma oscillations and that the 40-Hz oscillation circuit have specific inhibitory innervation to the low-gamma circuit.

Effects of Magnitude of Leading Stimulus on Prepulse Inhibition of Auditory Evoked Cerebral Responses: An Exploratory Study.

An abrupt change in a sound feature (test stimulus) elicits a specific cerebral response, which is attenuated by a weaker sound feature change (prepulse) preceding the test stimulus. As an exploratory study, we investigated whether and how the magnitude of the change of the prepulse affects the degree of prepulse inhibition (PPI). Sound stimuli were 650 ms trains of clicks at 100 Hz. The test stimulus was an abrupt sound pressure increase (by 10 dB) in the click train. Three consecutive clicks, weaker (-5 dB, -10 dB, -30 dB, or gap) than the baseline, at 30, 40, and 50 ms before the test stimulus, were used as prepulses. Magnetic responses to the ten types of stimuli (test stimulus alone, control, four types of tests with prepulses, and four types of prepulses alone) were recorded in 10 healthy subjects. The change-related N1m component, peaking at approximately 130 ms, and its PPI were investigated. The degree of PPI caused by the -5 dB prepulse was significantly weaker than that caused by other prepulses. The degree of PPI caused by further decreases in prepulse magnitude showed a plateau level between the -10 dB and gap prepulses. The results suggest that there is a physiologically significant range of sensory changes for PPI, which plays a role in the change detection for survival.

Conditioned Pain Modulation: Comparison of the Effects on Nociceptive and Non-nociceptive Blink Reflex.

Although conditioned pain modulation (CPM) is considered to represent descending pain inhibitory mechanisms triggered by noxious stimuli applied to a remote area, there have been no previous studies comparing CPM between pain and tactile systems. In this study, we compared CPM between the two systems objectively using blink reflexes. Intra-epidermal electrical stimulation (IES) and transcutaneous electrical stimulation (TS) were applied to the right skin area over the supraorbital foramen to evoke a nociceptive or a non-nociceptive blink reflex, respectively, in 15 healthy males. In the test session, IES or TS were applied six times and subjects reported the intensity of each stimulus on a numerical rating scale (NRS). Blink reflexes were measured using electromyography (R2). The first and second sessions were control sessions, while in the third session, the left hand was immersed in cold water at 10 °C as a conditioning stimulus. The magnitude of the R2 blink and NRS scores were compared among the sessions by 2-way ANOVA. Both the NRS score and nociceptive R2 were significantly decreased in the third session for IES, with a significant correlation between the two variables; whereas, TS-induced non-nociceptive R2 did not change among the sessions. Although the conditioning stimulus decreased the NRS score for TS, the CPM effect was significantly smaller than that for IES (p = 0.002). The present findings suggest the presence of a pain-specific CPM effect to a heterotopic noxious stimulus.

Synaptic Effect of Aδ-Fibers by Pulse-Train Electrical Stimulation.

Electrical stimulation of specific small fibers (Aδ- and C-fibers) is used in basic studies on nociception and neuropathic pain and to diagnose neuropathies. For selective stimulation of small fibers, the optimal stimulation waveform parameters are an important aspect together with the study of electrode design. However, determining an optimal stimulation condition is challenging, as it requires the characterization of the response of the small fibers to electrical stimulation. The perception thresholds are generally characterized using single-pulse stimulation based on the strength-duration curve. However, this does not account for the temporal effects of the different waveforms used in practical applications. In this study, we designed an experiment to characterize the effects of multiple pulse stimulation and proposed a computational model that considers electrostimulation of fibers and synaptic effects in a multiscale model. The measurements of perception thresholds showed that the pulse dependency of the threshold was an exponential decay with a maximum reduction of 55%. In addition, the frequency dependence of the threshold showed a U-shaped response with a reduction of 25% at 30 Hz. Moreover, the computational model explained the synaptic effects, which were also confirmed by evoked potential recordings. This study further characterized the activation of small fibers and clarified the synaptic effects, demonstrating the importance of waveform selection.