David M. Niddam

Contact heat evoked potentials as a valid means to study nociceptive pathways in human subjects

Contact heat evoked potentials (CHEPs) have been difficult to elicit due to slow temperature rise times. A recently developed heat-foil technology was used to elicit pain and CHEPs. Two groups of subjects were separately stimulated at the left arm with contact heat via one fast-acting (70 degrees C/s) heat-foil thermode. A set of CHEPs was recorded, each at three subjective intensities: warm; slight; and moderate pain. In CHEPs, the 3D topography exhibited four components: T3-T4/N450; Cz/N550; Cz/P750; and Pz/P1000. A vertex topography map was observed in the late Cz/N550-Cz/P750 and parietal topography in the very-late Pz/P1000 components. Consistent statistical values in the peak latencies and amplitudes were noted between consecutive investigations. The correlation between the pain intensity ratings and the major Cz/P750 amplitudes was highly significant in each study. Our validity tests suggested CHEPs to be useful for research and clinical applications in studying human pain activation related to thermal and nociceptive pathways.

Dipolar modelling of the scalp evoked potentials to painful contact heat stimulation of the human skin

Contact heat evoked potentials (CHEPs) were collected in 12 healthy subjects by stimulating the forearm skin with a couple of thermodes at a painful intensity. The stimulated area was 628 mm(2) and the repetition rate was 0.1 Hz. The electroencephalogram was recorded by 31 electrodes placed on the scalp according to an extended 10-20 System. A dipolar model explaining the scalp CHEP distribution was built by using the brain electrical source analysis. The model includes two dipoles located bilaterally in the perisylvian region, one dipole in the deep midline region and two dipoles located bilaterally in the deep temporal lobe. This dipolar model is very similar to that previously described to explain the topography of evoked potentials to radiant heat stimulation by laser pulses. Since laser stimuli activate the nociceptive fibres, the strong similarity of the cerebral dipoles activated by contact heat stimuli and by laser pulses suggests that only nociceptive inputs are involved in the scalp painful CHEP building. Therefore, CHEP recording can be useful for clinical examination of the nociceptive system.

Neuronal correlates in the modulation of placebo analgesia in experimentally-induced esophageal pain: A 3T-fMRI study

&NA; Visceral pain/discomfort is the cardinal complaints and treatment targets for functional gastrointestinal disorders (FGID). However, effective treatment for such pain is limited and often associated with high placebo effects. The mechanisms of placebo effects in visceral pain are unclear. We used functional neuroimaging to study the central representations of the placebo effect and its anticipation during esophageal pain in healthy adults. Fourteen subjects were enrolled. Pain extent, psychophysical inventories [Pain Catastrophizing Scale (PAS), visual analogue scale (VAS) and short‐form McGill questionnaire], and brain activity upon placebo intervention and upon anticipation were assessed in response to esophageal balloon distension. Large reductions of pain extent, VAS rating, short‐form McGill questionnaire scores, and brain activity in the visceral pain matrix [thalamus, somatosensory cortices, insula, prefrontal cortex (PFC), anterior cingulate cortex] were observed upon placebo treatment. The aforementioned brain areas and the bilateral amygdala were significantly correlated with decreased pain extent and VAS in response to placebo. The ventral lateral PFC (VLPFC) was associated with increased activity during anticipation of visceral pain. PAS cannot predict the placebo effect in visceral pain. In conclusion, pronounced placebo analgesia was coupled with prominent changes of brain activity in visceral pain matrix, which are thus likely involved in high placebo efficacy during the treatment of visceral pain in FGID. VLPFC activation during the anticipation of placebo analgesia suggests top‐down control in the modulation of pain experience.

Dipolar source modeling of somatosensory evoked potentials to painful and nonpainful median nerve stimulation

Dipolar source modeling might help in clarifying whether somatosensory evoked potentials (SEPs) after electrical stimulation at painful intensity contain any information related to the nociceptive processing. SEPs were recorded after left median nerve stimulation at three different intensities: intense but nonpainful (intensity 2); slightly painful (pain threshold; intensity 4); and moderately painful (intensity 6). Scalp SEPs at intensities 2, 4, and 6 were fitted by a five‐dipole model. When the strength modifications of the source activities up to 40 ms were examined across the different stimulus intensities, no significant difference was found. In the later epoch (40–200 ms), a posterior parietal dipole and two bilateral sources probably located in the second somatosensory (SII) areas increased significantly their dipole moments when the stimulus was increased from 2 to 4 and became painful. Since no difference was found when the stimulus intensity was increased from 4 to 6, the observed increase of the dipolar strengths is probably related to a variation of the stimulus quality (nonpainful vs. painful), rather than of the stimulus intensity per se. Our findings lead us to conclude that a large convergence of nociceptive and non‐nociceptive afferents probably occurs bilaterally in the SII areas.

Cerebral response to electric stimulation of the colon and abdominal skin in healthy subjects and patients with irritable bowel syndrome

Background: Visceral hyperalgesia may play an important part in the pathophysiology of the irritable bowel syndrome (IBS). We investigated the neuronal afferent pathways in healthy volunteers and IBS patients by recording evoked potentials (EPs) elicited by electrical stimulation of the colon and abdominal skin inside and outside the referred pain area. Methods: Six healthy subjects and nine IBS patients met the inclusion criteria. Morphology and topography of EPs to painful electrical stimuli were estimated in the rectosigmoid junction and on the skin inside/outside the referred pain areas. Results: The EPs to painful stimuli of the gut showed a shorter latency and a smaller amplitude of the first positive peak (P1) in the IBS group. The controls had a mid-latency frontal positive component after 100 ms, whereas no reliable early activation was seen in the IBS patients. In controls, a single late (> 150 ms) positive component was seen, whereas the late component was biphasic in the IBS group. The EPs to painful stimuli of the two skin areas differed in IBS patients, but not in controls. Conclusion: Differences in the EPs to electrical painful stimulation of the sigmoid colon and skin inside/outside the experimentally evoked referred pain area were seen comparing healthy subjects and IBS patients. The results indicate altered central nervous system responses.BACKGROUND Visceral hyperalgesia may play an important part in the pathophysiology of the irritable bowel syndrome (IBS). We investigated the neuronal afferent pathways in healthy volunteers and IBS patients by recording evoked potentials (EPs) elicited by electrical stimulation of the colon and abdominal skin inside and outside the referred pain area. METHODS Six healthy subjects and nine IBS patients met the inclusion criteria. Morphology and topography of EPs to painful electrical stimuli were estimated in the rectosigmoid junction and on the skin inside/outside the referred pain areas. RESULTS The EPs to painful stimuli of the gut showed a shorter latency and a smaller amplitude of the first positive peak (P1) in the IBS group. The controls had a mid-latency frontal positive component after 100 ms, whereas no reliable early activation was seen in the IBS patients. In controls, a single late (>150 ms) positive component was seen, whereas the late component was biphasic in the IBS group. The EPs to painful stimuli of the two skin areas differed in IBS patients, but not in controls. CONCLUSION Differences in the EPs to electrical painful stimulation of the sigmoid colon and skin inside/outside the experimentally evoked referred pain area were seen comparing healthy subjects and IBS patients. The results indicate altered central nervous system responses.

Contact heat evoked potentials to painful and non-painful stimuli: effect of attention towards stimulus properties

The study aim was to evaluate the effect of different attentional tasks on the amplitudes and latencies of painful and non-painful contact heat evoked potentials (CHEPs). CHEPs were recorded in 12 healthy subjects during two experimental conditions, in which attention was oriented towards the intensity and the distress caused by the stimuli and were compared with CHEPs recorded during a neutral condition. The painful heat stimulation produced a negative potential at Cz vertex with a latency around 540 ms (Cz/N540), a positive peak at Cz electrode around 730 ms (Cz/P730) and, lastly, a positive peak around 1000 ms (Pz/P1000) in the Pz traces. The Cz/P730 wave was significantly higher in amplitude only during the painful stimulation and is probably related to coding the nociceptive activity. Varying the attentional target towards different properties of the stimulus did not cause any significant change in CHEP responses amplitude and latencies compared with the neutral condition. Our results suggest that CHEPs represent a reliable functional measure of the nociceptive pathways and that they are generated by the activation of different cerebral areas involved in pain processing. The high activation level of each of these area or their spatial neighbouring might explain the strong similarity of CHEP components recorded during different attentional manipulations.

Spatial summation of pain processing in the human brain as assessed by cerebral event related potentials

To understand spatial summation of pain processing in the brain, we investigated the cerebral evoked responses to non-painful and painful contact heat stimulation (70 degrees C/s fast onset; intensity 2,4,6, corresponding to the individuals non-, slight and moderate pain) comparing one (1s) vs. two spots (2s) in 11 subjects while electroencephalographic signals were recorded. Significant spatial summation effects were shown only for the pain levels. For moderate pain, global field power examination isolated two peak activations for the vertex (Cz) N550 and P750 components. The single dipole modelling identified as likely the supplementary motor area, SMA area-6 source for N550, and posterior cingulate area-23 for P750. These source components showed a significantly faster (41.2 ms) latency and a shift in location from dorsal to ventral SMA of N550 toward cingulate area-31 between the 1s and 2s conditions. The temporal and spatial shift during spatial summation may reflect speeding up of the limbic affective reaction and prefrontal cognitive preparation in impending aversion and is deemed essential for integration of bodily sensations, such as pain.

Sensory gating, inhibition control and gamma oscillations in the human somatosensory cortex

Inhibiting the responses to irrelevant stimuli is an essential component of human cognitive function. Pre-attentive auditory sensory gating (SG), an attenuated neural activation to the second identical stimulus, has been found to be related to the performance of higher-hierarchical brain function. However, it remains unclear whether other cortical regions, such as somatosensory cortex, also possess similar characteristics, or if such a relationship is modality-specific. This study used magnetoencephalography to record neuromagnetic responses to paired-pulse electrical stimulation to median nerve in 22 healthy participants. Somatosensory SG ratio and cortical brain oscillations were obtained and compared with the behavioral performance of inhibition control, as evaluated by somatosensory and auditory Go-Nogo tasks. The results showed that somatosensory P35m SG ratio correlated with behavioral performance of inhibition control. Such relationship was also established in relation to the auditory Go-Nogo task. Finally, a higher frequency value of evoked gamma oscillations was found to relate to a better somatosensory SG ability. In conclusion, our data provided an empirical link between automatic cortical inhibition and behavioral performance of attentive inhibition control. This study invites further research on the relationships among gamma oscillations, neurophysiological indices, and behavioral performance in clinical populations in terms of SG or cortical inhibition.

Cerebral Dynamics of SEPs to Non-Painful and Painful Cutaneous Electrical Stimulation of the Thenar and Hypothenar

Early, middle and late latency somatosensory evoked potentials (SEPs) elicited by cutaneous electrical stimulation (painful vs. non-painful) of right and left hands were recorded. The aims were to study (1) if lifelong use of dominant right hand would result in different SEP topographies compared to non-dominant left hand stimulation, (2) if painful and non-painful stimuli resulted in different SEP activation patterns for the different latency components and (3) if these results were consistent between two areas of the hand. Electrical stimuli were applied cutaneously above the thenar and hypothenar muscles of the left and right hand. A two-way repeated measures ANOVA was used to test the effects of laterality and intensity for a given peak amplitude and latency. Statistical results yielded no significant difference in peak amplitude for either thenar and hypothenar between the two hands. In contrast, a significant difference in amplitude was observed for 6 components for each stimulus location when the two intensities were compared. These components were found at early, middle and late latencies. No significant latency shift was observed between the two hands. Only the P30 component showed a significant latency shift for both locations with the painful condition having the shorter latency. Thus, life-long use of the dominant hand does not generate detectable changes in cortical evoked activity to sensory input from the skin above thenar and hypothenar muscles. Several SEP components across the time course (0-400 ms) showed increased amplitude when the stimulus was increased from non-painful to painful intensity.

Automatic inhibitory function in the human somatosensory and motor cortices: An MEG-MRS study

While the automatic inhibitory function of the human cerebral cortex has been extensively investigated by means of electrophysiological recordings, the corresponding modulating neurochemical mechanisms remain unclear. We aimed to examine whether the primary somatosensory (SI) and primary motor cortical (MI) inhibitory function is associated with endogenous GABA levels. Eighteen young participants received paired-pulse and single-pulse electrical stimulation to the median nerve during magnetoencephalographic recordings. The SI sensory gating (SG), considered as an automatic inhibitory ability, was measured as the amplitude ratio of Stimulus 2 over Stimulus 1, in the paired-pulse paradigm. In addition, stimulus-induced beta activity, considered to originate from MI and also to be related to inhibitory function, was estimated using the single-pulse paradigm. The GABA+ concentration of the sensorimotor cortex was acquired from each subject by using magnetic resonance spectroscopy (MRS). A lower SG ratio in SI was significantly associated with an increased beta power in MI. More importantly, the beta rebound power, but not SI SG ratio, was positively correlated with GABA+ concentration. Our findings show a tight functional relationship between SI and MI during processing of automatic inhibition. GABA+ levels appear to be more closely related to the automatic inhibitory function of MI than SI.