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.

Prepulse Inhibition of the Auditory Off-Response: A Magnetoencephalographic Study.

A weak preceding sound stimulus attenuates the startle response evoked by an intense sound stimulus. Like startle reflexes, change-related auditory responses are suppressed by a weak leading stimulus (ie, a prepulse). We aim to examine whether a prepulse inhibits cerebral responses to the sound offset and how the prepulse magnitude affects the degree of the prepulse inhibition (PPI). Using magnetoencephalography, we recorded the Off-P50m elicited by an offset of a train sound of 100-Hz clicks in 12 healthy subjects. A single click slightly louder (+1.5, +3, or +5 dB) than the background sound of 80 dB was inserted 50 ms before the sound offset as a prepulse. We performed a dipole source analysis of the Off-P50m, and we measured its latency and amplitude using the source strength waveforms. The origin of the Off-P50m was estimated to be the auditory cortex on both hemispheres. The Off-P50m was clearly attenuated by the prepulses, and the degree of PPI was greater with a louder prepulse. The Off-P50m is considered to be a simple change-related response, which does not overlap with a processing of incoming sounds. Thus, the Off-P50m and its PPI comprise a valuable tool for investigating the neural inhibitory system.

Effects of acute hypoxia on human cognitive processing: a study using ERPs and SEPs.

Although hypoxia has the potential to impair the cognitive function, the effects of acute hypoxia on the high-order brain function (executive and/or inhibitory processing) and somatosensory ascending processing remain unknown. We tested the hypothesis that acute hypoxia impairs both motor executive and inhibitory processing and somatosensory ascending processing. Fifteen healthy subjects performed two sessions (sessions 1 and 2), consisting of electroencephalographic event-related potentials with somatosensory Go/No-go paradigms and somatosensory-evoked potentials (SEPs) under two conditions (hypoxia and normoxia) on different days. On 1 day, participants breathed room air in the first and second sessions of the experiment; on the other day, participants breathed room air in the first session, and 12% O2 in the second session. Acute hypoxia reduced the peak amplitudes of Go-P300 and No-go-P300, and delayed the peak latency of Go-P300. However, no significant differences were observed in the peak amplitude or latency of N140, behavioral data, or the amplitudes and latencies of individual SEP components between the two conditions. These results suggest that acute hypoxia impaired neural activity in motor executive and inhibitory processing, and delayed higher cognitive processing for motor execution, whereas neural activity in somatosensory processing was not affected by acute hypoxia.NEW & NOTEWORTHY Hypoxia has the potential to impair the cognitive function, but the effects of acute hypoxia on the cognitive function remain debatable. We investigated the effects of acute hypoxia on human cognitive processing using electroencephalographic event-related potentials and somatosensory-evoked potentials. Acute normobaric hypoxia impaired neural activity in motor executive and inhibitory processing, but no significant differences were observed in neural activity in somatosensory processing.

Effects of white noise on event-related potentials in somatosensory Go/No-go paradigms.

Exposure to auditory white noise has been shown to facilitate human cognitive function. This phenomenon is termed stochastic resonance, and a moderate amount of auditory noise has been suggested to benefit individuals in hypodopaminergic states. The present study investigated the effects of white noise on the N140 and P300 components of event-related potentials in somatosensory Go/No-go paradigms. A Go or No-go stimulus was presented to the second or fifth digit of the left hand, respectively, at the same probability. Participants performed somatosensory Go/No-go paradigms while hearing three different white noise levels (45, 55, and 65 dB conditions). The peak amplitudes of Go-P300 and No-go-P300 in ERP waveforms were significantly larger under 55 dB than 45 and 65 dB conditions. White noise did not affect the peak latency of N140 or P300, or the peak amplitude of N140. Behavioral data for the reaction time, SD of reaction time, and error rates showed the absence of an effect by white noise. This is the first event-related potential study to show that exposure to auditory white noise at 55 dB enhanced the amplitude of P300 during Go/No-go paradigms, reflecting changes in the neural activation of response execution and inhibition processing.

Effects of face/head and whole body cooling during passive heat stress on human somatosensory processing.

We herein investigated the effects of face/head and whole body cooling during passive heat stress on human somatosensory processing recorded by somatosensory-evoked potentials (SEPs) at C4' and Fz electrodes. Fourteen healthy subjects received a median nerve stimulation at the left wrist. SEPs were recorded at normothermic baseline (Rest), when esophageal temperature had increased by ~1.2°C (heat stress: HS) during passive heating, face/head cooling during passive heating (face/head cooling: FHC), and after HS (whole body cooling: WBC). The latencies and amplitudes of P14, N20, P25, N35, P45, and N60 at C4' and P14, N18, P22, and N30 at Fz were evaluated. Latency indicated speed of the subcortical and cortical somatosensory processing, while amplitude reflected the strength of neural activity. Blood flow in the internal and common carotid arteries (ICA and CCA, respectively) and psychological comfort were recorded in each session. Increases in esophageal temperature due to HS significantly decreased the amplitude of N60, psychological comfort, and ICA blood flow in the HS session, and also shortened the latencies of SEPs (all, P < 0.05). While esophageal temperature remained elevated, FHC recovered the peak amplitude of N60, psychological comfort, and ICA blood flow toward preheat baseline levels as well as WBC. However, the latencies of SEPs did not recover in the FHC and WBC sessions. These results suggest that impaired neural activity in cortical somatosensory processing during passive HS was recovered by FHC, whereas conduction velocity in the ascending somatosensory input was accelerated by increases in body temperature.

Broadened population-level frequency tuning in the auditory cortex of tinnitus patients.

Tinnitus is a phantom auditory perception without an external sound source and is one of the most common public health concerns that impair the quality of life of many individuals. However, its neural mechanisms remain unclear. We herein examined population-level frequency tuning in the auditory cortex of unilateral tinnitus patients with similar hearing levels in both ears using magnetoencephalography. We compared auditory-evoked neural activities elicited by a stimulation to the tinnitus and nontinnitus ears. Objective magnetoencephalographic data suggested that population-level frequency tuning corresponding to the tinnitus ear was significantly broader than that corresponding to the nontinnitus ear in the human auditory cortex. The results obtained support the hypothesis that pathological alterations in inhibitory neural networks play an important role in the perception of subjective tinnitus.NEW & NOTEWORTHY Although subjective tinnitus is one of the most common public health concerns that impair the quality of life of many individuals, no standard treatment or objective diagnostic method currently exists. We herein revealed that population-level frequency tuning was significantly broader in the tinnitus ear than in the nontinnitus ear. The results of the present study provide an insight into the development of an objective diagnostic method for subjective tinnitus.

Inhibition in the Human Auditory Cortex.

Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI) in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms) prepulse. The time course of the inhibition evaluated by prepulses presented at 10-800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20-60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse-evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful.

Encoding of frequency-modulation (FM) rates in human auditory cortex.

Frequency-modulated sounds play an important role in our daily social life. However, it currently remains unclear whether frequency modulation rates affect neural activity in the human auditory cortex. In the present study, using magnetoencephalography, we investigated the auditory evoked N1m and sustained field responses elicited by temporally repeated and superimposed frequency-modulated sweeps that were matched in the spectral domain, but differed in frequency modulation rates (1, 4, 16, and 64 octaves per sec). The results obtained demonstrated that the higher rate frequency-modulated sweeps elicited the smaller N1m and the larger sustained field responses. Frequency modulation rate had a significant impact on the human brain responses, thereby providing a key for disentangling a series of natural frequency-modulated sounds such as speech and music.

Hemispheric asymmetry of auditory mismatch negativity elicited by spectral and temporal deviants: a magnetoencephalographic study.

One of the major challenges in human brain science is the functional hemispheric asymmetry of auditory processing. Behavioral and neurophysiological studies have demonstrated that speech processing is dominantly handled in the left hemisphere, whereas music processing dominantly occurs in the right. Using magnetoencephalography, we measured the auditory mismatch negativity elicited by band-pass filtered click-trains, which deviated from frequently presented standard sound signals in a spectral or temporal domain. The results showed that spectral and temporal deviants were dominantly processed in the right and left hemispheres, respectively. Hemispheric asymmetry was not limited to high-level cognitive processes, but also originated from the pre-attentive neural processing stage represented by mismatch negativity.

Hierarchical neural encoding of temporal regularity in the human auditory cortex.

Temporal regularity provides an important cue for the identification of natural sounds. Here, we measured auditory evoked cortical magnetic fields to investigate the neural processing of temporal regularity that cannot be tonotopically represented in the auditory periphery. Auditory steady state responses (ASSR) and sustained fields (SF) elicited by 40 Hz amplitude modulated periodic and non-periodic noises were analyzed. Periodic noises of 40-, 20-, and 5-Hz were prepared in the form of repeating frozen noises where the same noise segment appears at either each period (40 Hz), every second period (20 Hz), or every eighth period (5 Hz) of amplitude modulation. Compared to non-periodic white noises, periodic noises with repetition rates of 5-, 20-, and 40-Hz caused significantly increased SF amplitudes in both hemispheres. ASSR amplitudes were significantly enhanced for 20- and 40-Hz periodic noises in the right hemisphere while no enhancement was observed for periodic noises in the left hemisphere. The observed variation of the regularity effect between evoked response components and hemispheres may reflect the differences in the temporal integration window lengths adopted between ASSR and SF generators and also between the right and left auditory pathways.

Neural adaptation to silence in the human auditory cortex: a magnetoencephalographic study.

INTRODUCTION: Previous studies demonstrated that a decrement in the N1m response, a major deflection in the auditory evoked response, with sound repetition was mainly caused by bottom-up driven neural refractory periods following brain activation due to sound stimulations. However, it currently remains unknown whether this decrement occurs with a repetition of silences, which do not induce refractoriness. METHODS: In the present study, we investigated decrements in N1m responses elicited by five repetitive silences in a continuous pure tone and by five repetitive pure tones in silence using magnetoencephalography. RESULTS: Repetitive sound stimulation differentially affected the N1m decrement in a sound type-dependent manner; while the N1m amplitude decreased from the 1st to the 2nd pure tone and remained constant from the 2nd to the 5th pure tone in silence, a gradual decrement was observed in the N1m amplitude from the 1st to the 5th silence embedded in a continuous pure tone. CONCLUSIONS: Our results suggest that neural refractoriness may mainly cause decrements in N1m responses elicited by trains of pure tones in silence, while habituation, which is a form of the implicit learning process, may play an important role in the N1m source strength decrements elicited by successive silences in a continuous pure tone.

History of silence affects auditory evoked fields regardless of intervening sounds: a magnetoencephalographic study.

The amplitudes of auditory evoked N1 m responses are known to depend on the length of the pre-stimulus silent interval. However, it remains unknown whether pre-penultimate silent intervals affect the auditory evoked responses elicited by test stimuli. In the present study, we investigated the N1 m responses elicited by a train of four successive tones with a silent interval of 1 s subsequent to that with a 0.25-, 0.5-, 2- or 4-s silent interval using magnetoencephalography. The results obtained demonstrated that the N1 m source strength decreased as the pre-penultimate silent interval became shorter. A history of silences had a significant impact on the N1 m source strength. Human brain activity that is modulated by silence history may play an important role in encoding a series of sound streams that include silences, such as speech and music.

Echoic memory: investigation of its temporal resolution by auditory offset cortical responses.

Previous studies showed that the amplitude and latency of the auditory offset cortical response depended on the history of the sound, which implicated the involvement of echoic memory in shaping a response. When a brief sound was repeated, the latency of the offset response depended precisely on the frequency of the repeat, indicating that the brain recognized the timing of the offset by using information on the repeat frequency stored in memory. In the present study, we investigated the temporal resolution of sensory storage by measuring auditory offset responses with magnetoencephalography (MEG). The offset of a train of clicks for 1 s elicited a clear magnetic response at approximately 60 ms (Off-P50m). The latency of Off-P50m depended on the inter-stimulus interval (ISI) of the click train, which was the longest at 40 ms (25 Hz) and became shorter with shorter ISIs (2.5∼20 ms). The correlation coefficient r2 for the peak latency and ISI was as high as 0.99, which suggested that sensory storage for the stimulation frequency accurately determined the Off-P50m latency. Statistical analysis revealed that the latency of all pairs, except for that between 200 and 400 Hz, was significantly different, indicating the very high temporal resolution of sensory storage at approximately 5 ms.

Meditation reduces pain-related neural activity in the anterior cingulate cortex, insula, secondary somatosensory cortex, and thalamus.

Recent studies have shown that meditation inhibits or relieves pain perception. To clarify the underlying mechanisms for this phenomenon, neuroimaging methods, such as functional magnetic resonance imaging, and neurophysiological methods, such as magnetoencephalography and electroencephalography, have been used. However, it has been difficult to interpret the results, because there is some paradoxical evidence. For example, some studies reported increased neural responses to pain stimulation during meditation in the anterior cingulate cortex (ACC) and insula, whereas others showed a decrease in these regions. There have been inconsistent findings to date. Moreover, in general, since the activities of the ACC and insula are correlated with pain perception, the increase in neural activities during meditation would be related to the enhancement of pain perception rather than its reduction. These contradictions might directly contribute to the 'mystery of meditation.' In this review, we presented previous findings for brain regions during meditation and the anatomical changes that occurred in the brain with long-term meditation training. We then discussed the findings of previous studies that examined pain-related neural activity during meditation. We also described the brain mechanisms responsible for pain relief during meditation, and possible reasons for paradoxical evidence among previous studies. By thoroughly overviewing previous findings, we hypothesized that meditation reduces pain-related neural activity in the ACC, insula, secondary somatosensory cortex, and thalamus. We suggest that the characteristics of the modulation of this activity may depend on the kind of meditation and/or number of years of experience of meditation, which were associated with paradoxical findings among previous studies that investigated pain-related neural activities during meditation.

Differential effects of temporal regularity on auditory-evoked response amplitude: a decrease in silence and increase in noise.

BACKGROUND: In daily life, we are continuously exposed to temporally regular and irregular sounds. Previous studies have demonstrated that the temporal regularity of sound sequences influences neural activity. However, it remains unresolved how temporal regularity affects neural activity in noisy environments, when attention of the listener is not focused on the sound input. METHODS: In the present study, using magnetoencephalography we investigated the effects of temporal regularity in sound signal sequencing (regular vs. irregular) in silent versus noisy environments during distracted listening. RESULTS: The results demonstrated that temporal regularity differentially affected the auditory-evoked N1m response depending on the background acoustic environment: the N1m amplitudes elicited by the temporally regular sounds were smaller in silence and larger in noise than those elicited by the temporally irregular sounds. CONCLUSIONS: Our results indicate that the human auditory system is able to involuntarily utilize temporal regularity in sound signals to modulate the neural activity in the auditory cortex in accordance with the surrounding acoustic environment.

Task-related changes in functional properties of the human brain network underlying attentional control.

Previous studies have demonstrated task-related changes in brain activation and inter-regional connectivity but the temporal dynamics of functional properties of the brain during task execution is still unclear. In the present study, we investigated task-related changes in functional properties of the human brain network by applying graph-theoretical analysis to magnetoencephalography (MEG). Subjects performed a cue-target attention task in which a visual cue informed them of the direction of focus for incoming auditory or tactile target stimuli, but not the sensory modality. We analyzed the MEG signal in the cue-target interval to examine network properties during attentional control. Cluster-based non-parametric permutation tests with the Monte-Carlo method showed that in the cue-target interval, beta activity was desynchronized in the sensori-motor region including premotor and posterior parietal regions in the hemisphere contralateral to the attended side. Graph-theoretical analysis revealed that, in beta frequency, global hubs were found around the sensori-motor and prefrontal regions, and functional segregation over the entire network was decreased during attentional control compared to the baseline. Thus, network measures revealed task-related temporal changes in functional properties of the human brain network, leading to the understanding of how the brain dynamically responds to task execution as a network.

Effects of acute nicotine on prepulse inhibition of auditory change-related cortical responses.

Prepulse inhibition (PPI) of startle is a measure of inhibitory function in which a weak leading stimulus suppresses the startle response to an intense stimulus. Usually, startle blink reflexes to an intense sound are used for measuring PPI. A recent magnetoencephalographic study showed that a similar phenomenon is observed for auditory change-related cortical response (Change-N1m) to an abrupt change in sound features. It has been well established that nicotine enhances PPI of startle. Therefore, in the present magnetoencephalographic study, the effects of acute nicotine on PPI of the Change-N1m were studied in 12 healthy subjects (two females and 10 males) under a repeated measures and placebo-controlled design. Nicotine (4 mg) was given as nicotine gum. The test Change-N1m response was elicited with an abrupt increase in sound pressure by 6 dB in a continuous background sound of 65 dB. PPI was produced by an insertion of a prepulse with a 3-dB-louder or 6-dB-weaker sound pressure than the background 75 ms before the test stimulus. Results show that nicotine tended to enhance the test Change-N1m response and significantly enhanced PPI for both prepulses. Therefore, nicotine's enhancing effect on PPI of the Change-N1m was similar to that on PPI of the startle. The present results suggest that the two measures share at least some mechanisms.

Cortico-subcortical activation patterns for itch and pain imagery.

The imagery of itch and pain evokes emotional responses and covert motor responses (scratching to itch and withdrawal to pain). This suggests some similarity in cerebral mechanisms. However, itch is more socially contagious than pain, as evidenced by the fact that scratching behaviors can be easily initiated by watching itch-inducing situations, whereas withdrawal is less easily initiated by watching painful situations. Thus, we assumed that the cerebral mechanisms of itch imagery partly differ from those of pain imagery in particular with respect to motor regions. We addressed this issue in 18 healthy subjects using functional magnetic resonance imaging. The subjects were instructed to imagine itch and pain sensations in their own bodies while viewing pictures depicting stimuli associated with these sensations. Itch and pain imagery activated the anterior insular cortex (aIC) and motor-related regions such as supplementary motor area, basal ganglia, thalamus, and cerebellum. Activity in these regions was not significantly different between itch and pain imagery. However, functional connectivity between motor-related regions and the aIC showed marked differences between itch and pain imagery. Connectivity with the aIC was stronger in the primary motor and premotor cortices during pain imagery and stronger in the globus pallidus during itch imagery. These findings indicate that brain regions associated with imagery of itch are the same as those involved in imagery of pain, but their functional networks differ. These differences in brain networks may explain why motor responses to itch are more socially contagious than those related to pain.

Prepulse inhibition of auditory change-related cortical responses.

BACKGROUND: Prepulse inhibition (PPI) of the startle response is an important tool to investigate the biology of schizophrenia. PPI is usually observed by use of a startle reflex such as blinking following an intense sound. A similar phenomenon has not been reported for cortical responses. RESULTS: In 12 healthy subjects, change-related cortical activity in response to an abrupt increase of sound pressure by 5 dB above the background of 65 dB SPL (test stimulus) was measured using magnetoencephalography. The test stimulus evoked a clear cortical response peaking at around 130 ms (Change-N1m). In Experiment 1, effects of the intensity of a prepulse (0.5 ~ 5 dB) on the test response were examined using a paired stimulation paradigm. In Experiment 2, effects of the interval between the prepulse and test stimulus were examined using interstimulus intervals (ISIs) of 50 ~ 350 ms. When the test stimulus was preceded by the prepulse, the Change-N1m was more strongly inhibited by a stronger prepulse (Experiment 1) and a shorter ISI prepulse (Experiment 2). In addition, the amplitude of the test Change-N1m correlated positively with both the amplitude of the prepulse-evoked response and the degree of inhibition, suggesting that subjects who are more sensitive to the auditory change are more strongly inhibited by the prepulse. CONCLUSIONS: Since Change-N1m is easy to measure and control, it would be a valuable tool to investigate mechanisms of sensory gating or the biology of certain mental diseases such as schizophrenia.

Memory-based pre-attentive auditory N1 elicited by sound movement.

Quickly detecting changes in the surrounding environment is one of the most important functions of sensory processing. Comparison of a new event with preceding sensory conditions is necessary for the change-detection process. A sudden change in a continuous sound elicits auditory evoked potentials that peak approximately 100 ms after the onset of the change (Change-N1). In the present study, we recorded Change-N1 under an oddball paradigm in 19 healthy subjects using an abruptly moving sound (SM-stimulus) as a deviant stimulus and investigated effects of the probability of the SM-stimulus to reveal whether Change-N1 is a memory-based response. We compared the amplitude and latency of Change-N1 elicited by the SM-stimulus among three probability conditions (33, 50 and 100%). As the probability of the SM-stimulus decreased, the amplitude of Change-N1 increased and its latency decreased. The present results indicate that the preceding sensory history affects Change-N1 elicited by the SM-stimulus.