Yohei Tamura

Electrophysiological studies on human pain perception

OBJECTIVE We reviewed the recent progress in electrophysiological studies using electroencephalography (EEG), magnetoencephalography (MEG) and repetitive transcranial magnetic stimulation (rTMS) on human pain perception. METHODS For recording activities following A delta fiber stimulation relating to first pain, several kinds of lasers such as CO2, Tm:YAG and argon lasers are now widely used. The activity is frequently termed laser evoked potential (LEP), and we reviewed previous basic and clinical reports on LEP. We also introduced our new method, epidermal stimulation (ES), which is useful for recording brain activities by the signals ascending through A delta fibers. For recording activities following C fiber stimulation relating to second pain, several methods have been used but weak CO2 laser stimuli applied to tiny areas of the skin were recently used. RESULTS EEG and MEG findings following C fiber stimulation were similar to those following A delta fiber stimulation except for a longer latency. Finally, we reviewed the effect of rTMS on acute pain perception. rTMS alleviated acute pain induced by intracutaneous injection of capsaicin, which activated C fibers, but it enhanced acute pain induced by laser stimulation, which activated A delta fibers. CONCLUSIONS One promising approach in the near future is to analyze the change of a frequency band. This method will probably be used for evaluation of continuous tonic pain such as cancer pain, which evoked response studies cannot evaluate.

Effects of 1-Hz repetitive transcranial magnetic stimulation on acute pain induced by capsaicin.

&NA; The aim of this study is to investigate the efficacy of 1‐Hz repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) on acute pain induced by intradermal capsaicin injection and to elucidate its mechanisms by single‐photon emission computed tomography (SPECT). We compared time courses of a subjective scale of pain induced by intradermal capsaicin injection in seven normal subjects under three different conditions: rTMS over M1, sham stimulation, and control condition (natural course of acute pain without any stimulation). In ten normal subjects, using SPECT, we also studied differences in regional cerebral blood flow (rCBF) after capsaicin injection between two conditions: rTMS over M1 and the control condition. rTMS over M1 induced earlier recovery from acute pain compared with the sham or control conditions. Under rTMS over the right M1 condition compared with the control condition, the SPECT study demonstrated a significant relative rCBF decrease in the right medial prefrontal cortex (MPFC) corresponding to Brodmann area (BA) 9, and a significant increase in the caudal part of the right anterior cingulate cortex (ACC) corresponding to BA24 and the left premotor area (BA6). A region‐of‐interest analysis showed significant correlation between pain reduction and rCBF changes in both BA9 and BA24. We conclude that rTMS over M1 should have beneficial effects on acute pain, and its effects must be caused by functional changes of MPFC and caudal ACC.

Pain processing within the primary somatosensory cortex in humans

To investigate the processing of noxious stimuli within the primary somatosensory cortex (SI), we recorded magnetoencephalography following noxious epidermal electrical stimulation (ES) and innocuous transcutaneous electrical stimulation (TS) applied to the dorsum of the left hand. TS activated two sources sequentially within SI: one in the posterior bank of the central sulcus and another in the crown of the postcentral gyrus, corresponding to Brodmanns areas 3b and 1, respectively. Activities from area 3b consisted of 20‐ and 30‐ms responses. Activities from area 1 consisted of three components peaking at 26, 36 and 49 ms. ES activated one source within SI whose location and orientation were similar to those of the TS‐activated area 1 source. Activities from this source consisted of three components peaking at 88, 98 and 109 ms, later by 60 ms than the corresponding TS responses. ES and TS subsequently activated a similar region in the upper bank of the sylvian fissure, corresponding to the secondary somatosensory cortex (SII). The onset latency of the SII activity following ES (109 ms) was later by 29 ms than that of the first SI response (80 ms). Likewise, the onset latency of SII activity following TS (52 ms) was later by 35 ms than that of area 1 of SI (17 ms). Therefore, our results showed that the processing of noxious and innocuous stimuli is similar with respect to the source locations and activation timings within SI and SII except that there were no detectable activations within area 3b following noxious stimulation.

Movements modulate cortical activities evoked by noxious stimulation

&NA; To evaluate the effects of movement on cortical activities evoked by noxious stimulation, we recorded magnetoencephalography following noxious YAG laser stimulation applied to the dorsum of the left hand in normal volunteers. Results of the present study can be summarized as follows: (1) active movement of the hand ipsilateral to the side of noxious stimulation resulted in significant attenuation of both primary and secondary somatosensory cortices (SI and SII) in the hemisphere contralateral to the stimulated hand (cSI and cSII). Activity in the hemisphere ipsilateral to the side of stimulation (iSII) was not affected. (2) Active movement of the hand contralateral to the side of noxious stimulation resulted in significant attenuation of cSII. Activity in cSI and iSII was not affected. (3) Passive movement of the hand ipsilateral to the side of noxious stimulation resulted in significant attenuation of cSI. Activity in cSII and iSII was not affected. (4) Visual analogue scale (VAS) changes showed a similar pattern to the amplitude changes of cSII. These results suggest that activities in three regions are modulated by movements differently. Inhibition in cSI was considered to be mainly due to an interaction in SI by the signals ascending from the stimulated and movement hand. Inhibition in cSII was considered to be mainly due to particular brain activities relating to motor execution and/or movement execution associated with a specific attention effect. In addition, since VAS changes showed a similar relationship with the amplitude changes of cSII, cSII may play a role in pain perception.

Sensory perception during sleep in humans: a magnetoencephalograhic study

We reported the changes of brain responses during sleep following auditory, visual, somatosensory and painful somatosensory stimulation by using magnetoencephalography (MEG). Surprisingly, very large changes were found under all conditions, although the changes in each were not the same. However, there are some common findings. Short-latency components, reflecting the primary cortical activities generated in the primary sensory cortex for each stimulus kind, show no significant change, or are slightly prolonged in latency and decreased in amplitude. These findings indicate that the neuronal activities in the primary sensory cortex are not affected or are only slightly inhibited during sleep. By contrast, middle- and long-latency components, probably reflecting secondary activities, are much affected during sleep. Since the dipole location is changed (auditory stimulation), unchanged (somatosensory stimulation) or vague (visual stimulation) between the state of being awake and asleep, different regions responsible for such changes of activity may be one explanation, although the activated regions are very close to each other. The enhancement of activities probably indicates two possibilities, an increase in the activity of excitatory systems during sleep, or a decrease in the activity of some inhibitory systems, which are active in the awake state. We have no evidence to support either, but we prefer the latter, since it is difficult to consider why neuronal activities would be increased during sleep.

Higher anticipated force required a stronger inhibitory process in go/nogo tasks

OBJECTIVE We investigated the effect of the inhibitory process with increasing muscle force on event-related potentials (ERPs) and motor evoked potentials (MEPs). METHODS The subjects performed a S1-S2 paradigm with go/nogo tasks. S1 was an auditory tone burst, and S2 was an electrical stimulation applied to the second (go stimuli) or fifth digit (nogo stimuli) of the left hand. The recordings were conducted at 3 force levels; 10, 30 and 50% maximal voluntary contraction (MVC). After the presentation of S2, the subjects were instructed to adjust their force level to match the target line with a force trajectory line in only the go trials. RESULTS Nogo-N140 was significantly more negative in amplitude than go-N140 in all conditions, and became larger with increasing muscle force. The MEP, which was recorded at 150 ms after S2, became significantly smaller with increasing muscle force in nogo trials, whereas it became larger in go trials. CONCLUSIONS Our results indicated that stronger inhibitory cerebral activity was needed for a nogo stimulus, in the case where a stronger response was needed for a go stimulus. SIGNIFICANCE The present study showed a significant relationship between cortical inhibitory process and muscle force.

Effects of ISI and stimulus probability on event-related go/nogo potentials after somatosensory stimulation

The present study investigated the characteristics of the middle-latency negative potential of event-related potentials (ERPs) using somatosensory go/nogo tasks. We manipulated interstimulus interval (ISI) in Experiment 1 and stimulus probability in Experiment 2 and analyzed the subtracted difference waveform resulting from subtraction of the ERP evoked by the go stimulation from that evoked by the nogo stimulation. In Experiment 1, the peak latency of negativity became significantly longer as the ISI increased, but the peak amplitude was unchanged. The reaction time (RT) was longer with increasing ISI. In Experiment 2, manipulation of the stimulus probability yielded an increase in peak amplitude with decreasing probability of the nogo stimulus, but did not affect the latency. The RT increased as the probability of a nogo stimulus rose. Because manipulation of the ISI and stimulus probability elicited different brain activities, we hypothesized that manipulation of the ISI elicited a delay of the stimulus evaluation process including response inhibition, and that stimulus probability significantly affected the strength of the response inhibition process.

Facilitation of Aδ-fiber-mediated acute pain by repetitive transcranial magnetic stimulation

Background: Repetitive transcranial magnetic stimulation (rTMS) of the motor cortex modulates acute and chronic pain perception. The authors previously showed that rTMS over the primary motor cortex (M1) inhibited capsaicin-induced acute pain ascending through C-fibers. Objective: To investigate the effects of 1-Hz rTMS over M1 on acute experimentally induced pain mediated by Aδ-fibers (i.e., another type of acute pain). Methods: The authors examined whether rTMS over M1 affected laser evoked potentials (LEPs) in 13 normal subjects using thulium: yttrium-aluminum-garnet laser stimulation. Subjective pain-rating scores and LEPs obtained under three different conditions—rTMS, realistic sham stimulation, and a control condition with no stimulation—were compared. Results: The authors found that 1-Hz rTMS over M1 significantly aggravated the subjective pain and enhanced the N2-P2 amplitudes compared with the sham or control sessions. Because the pain-rating scores and the N2-P2 amplitudes correlated positively, the N2-P2 amplitudes in the present study can be regarded as the cortical correlate of subjective pain. Conclusions: Together with the authors’ previous study on C-fiber pain, this facilitatory effect of repetitive transcranial magnetic stimulation on Aδ-fiber-mediated further strengthens the notion of a relationship between repetitive transcranial magnetic stimulation over M1 and pain perception.

Functional relationship between human rolandic oscillations and motor cortical excitability : an MEG study

Synchronization and desynchronization of the neural rhythm in the brain play an important role in the orchestration of perception, motor action and conscious experience. Based on the results of electrocorticographic and magnetoencephalographic (MEG) recordings, it has been considered that human rolandic oscillations originate in the anterior bank of the central sulcus (20‐Hz rhythm) and the postcentral cortex (10‐Hz rhythm): the 20‐Hz oscillation is closely related to motor function, while the 10‐Hz rhythm is attributed mainly to sensory function. To test whether the rolandic oscillations are functionally relevant to the motor cortical excitability, we examined effects of 1‐Hz repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex (M1) on movement‐related changes of the rolandic oscillations in 12 normal subjects. MEG data recorded during brisk extension of the right index finger in two different sessions (with and without rTMS conditioning) were compared. Motor‐evoked potential (MEP) of the right hand muscle was also measured before and after rTMS to assess the motor cortical excitability. We found that 1‐Hz rTMS over M1 significantly reduced the movement‐related rebound of the 20‐Hz oscillation in association with decreased motor cortical excitability. In particular, movement‐related rebound of the 20‐Hz rhythm was closely tied with motor cortical excitability. These findings further strengthen the notion of functional relevance of 20‐Hz cortical oscillation to motor cortical excitability. In the framework of previous studies, the decrease in movement‐related rebound may be regarded as a compensatory reaction to the inhibited cortical activity.

Evoked magnetic fields following noxious laser stimulation of the thigh in humans

Primary somatosensory cortex (SI) and posterior parietal cortex (PPC) are activated by noxious stimulation. In neurophysiological studies using magnetoencephalography (MEG), however, it has been difficult to separate the activity in SI from that in PPC following stimulation of the upper limb, since the hand area of SI is very close to PPC. Therefore, we investigated human pain processing using MEG following the application of a thulium-YAG laser to the left thigh to separate the activation of SI and PPC, and to clarify the time course of the activities involved. The results indicated that cortical activities were recorded around SI, contralateral secondary somatosensory cortex (cSII), ipsilateral secondary somatosensory cortex (iSII), and PPC between 150-185 ms. The precise location of PPC was indicated to be the inferior parietal lobule (IPL), corresponding to Brodmanns area 40. The mean peak latencies of SI, cSII, iSII and IPL were 152, 170, 181, and 183 ms, respectively. This is the first study to clarify the time course of the activities of SI, SII, and PPC in human pain processing using MEG.