Domenica Le Pera

Inhibition of motor system excitability at cortical and spinal level by tonic muscle pain

OBJECTIVE To assess whether the motor system excitability can be modified by experimental tonic pain induced either in muscles or in subcutis. METHODS Transcranial magnetic stimulation of the left primary motor cortex was used to record motor evoked potentials (MEPs) from the right abductor digiti minimi (ADM) muscle. Recordings were made before, during and after experimental pain induced by (1) injection of hypertonic (5%) saline into the right ADM, the right first dorsal interosseum (FDI) and the left ADM muscles, and (2) injection of hypertonic saline in the subcutaneous region of the right ADM. Both MEPs and H-reflex were recorded also from the right flexor carpi radialis (FCR) before, during and after muscle pain. RESULTS MEPs recorded from the ADM muscle were significantly reduced in amplitude during pain induced in the right ADM and right FDI muscles, but not during pain in the left ADM muscle or during subcutaneous pain. This inhibitory effect was observed during the peak-pain and persisted also after the disappearance of the pain sensation. In the FCR muscle, the MEP inhibition was observed during the peak-pain, while a significant reduction of the H-reflexs amplitude was observed starting 1 min after the peak-pain. CONCLUSIONS Tonic muscle pain can inhibit the motor system. The motor cortex inhibition observed at an early phase is followed by a reduction of the excitability of both cortical and spinal motoneurones.

Sources of cortical responses to painful CO2 laser skin stimulation of the hand and foot in the human brain

OBJECTIVES To investigate whether the same dipolar model could explain the scalp CO(2) laser evoked potential (LEP) distribution after either hand or foot skin stimulation. METHODS LEPs were recorded in 14 healthy subjects after hand and foot skin stimulation and brain electrical source analysis of responses obtained in each individual was performed. RESULTS A 5 dipolar sources model explained the scalp LEP topography after both hand and foot stimulation. In particular, we showed that the co-ordinates of the two earliest activated dipoles were compatible with source locations in the upper bank of the Sylvian fissure on both sides. These sources did not change their location when the stimulation site was moved from the upper to the lower limb. The other 3 dipoles of our model were activated in the late LEP latency range with a biphasic profile and a location compatible with activation of the cingulate gyrus and deep temporo-insular structures. CONCLUSIONS The dipolar model previously proposed for the hand stimulation LEPs can also satisfactorily explain the LEP distribution obtained after foot stimulation. The earliest activated Sylvian dipolar sources did not change their location when the upper or lower limb was stimulated, as expected from the close projections of hand and foot in the second somatosensory area. No source in the primary somatosensory area was necessary to model the scalp topography of LEPs to hand and foot stimulation.

Learning potentiates neurophysiological and behavioral placebo analgesic responses.

Abstract Expectation and conditioning are supposed to be the two main psychological mechanisms for inducing a placebo response. Here, we further investigate the effects of both expectation, which was induced by verbal suggestion alone, and conditioning at the level of N1 and N2–P2 components of CO2 laser‐evoked potentials (LEPs) and subjective pain reports. Forty‐four healthy volunteers were pseudorandomly assigned to one of three experimental groups: Group 1 was tested with verbal suggestion alone, Group 2 was tested with a conditioning procedure, whereby the intensity of painful stimulation was reduced surreptitiously, so as to make the volunteers believe that the treatment was effective, Group 3 was a control group that allowed us to rule out phenomena of sensitization and/or habituation. Pain perception was assessed according to a Numerical Rating Scale (NRS) ranging from 0 = no pain sensation to 10 = maximum imaginable pain. Both verbal suggestions (Group 1) and conditioning (Group 2) modified the N2–P2 complex, but not the N1 component of LEPs. However, the suggestion‐induced LEP changes occurred without subjective perception of pain decrease. Conversely, the N2–P2 amplitude changes that were induced by the conditioning procedure were associated with the subjective perception of pain reduction. Compared to natural history, conditioning produced more robust reductions of LEP amplitudes than verbal suggestions alone. Overall, these findings indicate that prior positive experience plays a key role in maximizing both behavioral and neurophysiological placebo responses, emphasizing that the placebo effect is a learning phenomenon which affects the early central nociceptive processing.

Inhibition of the human primary motor area by painful heat stimulation of the skin

OBJECTIVE To prove whether painful cutaneous stimuli can affect specifically the motor cortex excitability. METHODS The electromyographic (EMG) responses, recorded from the first dorsal interosseous muscle after either transcranial magnetic or electric anodal stimulation of the primary motor (MI) cortex, was conditioned by both painful and non-painful CO2 laser stimuli delivered on the hand skin. RESULTS Painful CO2 laser stimuli reduced the amplitude of the EMG responses evoked by the transcranial magnetic stimulation of both the contralateral and ipsilateral MI areas. This inhibitory effect followed the arrival of the nociceptive inputs to cerebral cortex. Instead, the EMG response amplitude was not significantly modified either when it was evoked by the motor cortex anodal stimulation or when non-painful CO2 laser pulses were used as conditioning stimuli. CONCLUSIONS Since the magnetic stimulation leads to transynaptic activation of pyramidal neurons, while the anodal stimulation activates directly cortico-spinal axons, the differential effect of the noxious stimuli on the EMG responses evoked by the two motor cortex stimulation techniques suggests that the observed inhibitory effect has a cortical origin. The bilateral cortical representation of pain explains why the painful CO2 laser stimuli showed a conditioning effect on MI area of both hemispheres. Non-painful CO2 laser pulses did not produce any effect, thus suggesting that the reduction of the MI excitability was specifically due to the activation of nociceptive afferents.

Abnormal processing of the nociceptive input in Parkinson's disease : A study with CO2 laser evoked potentials

&NA; Since a number of patients with Parkinson’s Disease (PD) complain of painful sensations, we studied whether the central processing of nociceptive inputs is abnormal in PD. To test this hypothesis, we recorded scalp CO2 laser evoked potentials (LEPs) to hand skin stimulation in 18 pain‐free PD patients with unilateral bradykinetic‐rigid syndrome (hemiparkinson) during the off state and in 18 healthy subjects. This technique allows us to explore non‐invasively the functional status of some cerebral structures involved in nociceptive input processing. In both PD patients and control subjects, CO2 laser stimulation gave rise to a main negative N2 potential followed by a positive P2 response at vertex peaking at a latency of about 200 and 300 ms, respectively. These potentials are thought to originate from several brain structures devoted to nociceptive input processing, including the cingulate gyrus and insula. PD patients and normal subjects showed comparable N2 and P2 latencies, whereas the N2/P2 peak‐to‐peak amplitude was significantly lower in PD patients (regardless of the clinically affected body side) than in controls. LEPs were even recorded after acute L‐dopa administration in 7 additional PD patients. L‐dopa administration yielded no significant change in N2/P2 amplitude as compared to the off state. These results suggest an abnormal nociceptive input processing in pain‐free PD patients which appears to be independent of clinical expression of parkinsonian motor signs and is not affected by dopaminergic stimulation.

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.

Dipolar sources of the early scalp somatosensory evoked potentials to upper limb stimulation. Effect of increasing stimulus rates.

Abstract Brain electrical source analysis (BESA) of the scalp electroencephalographic activity is well adapted to distinguish neighbouring cerebral generators precisely. Therefore, we performed dipolar source modelling in scalp medium nerve somatosensory evoked potentials (SEPs) recorded at 1.5-Hz stimulation rate, where all the early components should be identifiable. We built a four-dipole model, which was issued from the grand average, and applied it also to recordings from single individuals. Our model included a dipole at the base of the skull and three other perirolandic dipoles. The first of the latter dipoles was tangentially oriented and was active at the same latencies as the N20/P20 potential and, with opposite polarity, the P24/N24 response. The second perirolandic dipole showed an initial peak of activity slightly earlier than that of the N20/P20 dipolar source and, later, it was active at the same latency as the central P22 potential. Lastly, the third perirolandic dipole exaplaining the fronto-central N30 potential scalp distribution was constantly more posterior than the first one. In order to evaluate the effect of an increasing repetition frequency on the activity of SEP dipolar sources, we applied the model built from 1.5-Hz SEPs to traces recorded at 3-Hz and 10-Hz repetition rates. We found that the 10-Hz stimulus frequency reduced selectively the later of the two activity phases of the first perirolandic dipole. The decrement in strength of this dipolar source can be explained if we assume that: (a) the later activity of the first perirolandic dipole can represent the inhibitory phase of a “primary response”; (b) two different clusters of cells generate the opposite activities of the tangential perirolandic dipole. An additional finding in our model was that two different perirolandic dipoles contribute to the centro-parietal N20 potential generation.

Characterizing somatosensory evoked potential sources with dipole models: Advantages and limitations

Several methods have been developed to investigate the cerebral generators of scalp somatosensory evoked potentials (SEPs), because simple visual inspection of the electroencephalographic signal does not allow for immediate identification of the active brain regions. When the neurons fired by the afferent inputs are closely grouped, as usually occurs in SEP generation, they can be represented as a dipole, that is, as a linear source with two opposite poles. Several techniques for dipolar source modeling, which use different algorithms, have been employed to build source models of early, middle‐latency, and late cognitive SEPs. Modifications of SEP dipolar activities after experimental maneuvers or in pathological conditions have also been observed. Although the effectiveness of dipolar source analysis should not be overestimated due to the intrinsic limitations of the approach, dipole modeling provides a means to assess SEPs in terms of cerebral sources and voltage fields that they produce over the head.

Short-term plastic changes of the human nociceptive system following acute pain induced by capsaicin.

OBJECTIVE To investigate possible neuroplastic changes induced by pain in cerebral areas devoted to nociceptive input processing. METHODS CO(2) laser-evoked potentials (LEPs) were recorded from 10 healthy subjects after stimulation of the right and left hand dorsum. Acute pain was obtained by topical application of capsaicin on the skin of right hand dorsum. LEPs were recorded after right and left hand stimulation before capsaicin, at the peak pain and 10-20 min after capsaicin removal. Right hand LEPs were evoked by laser stimuli delivered over the zone of secondary hyperalgesia during capsaicin and on both the zones of primary and secondary hyperalgesia after capsaicin removal. RESULTS After right hand stimulation, the vertex LEPs, which are generated in the cingulate cortex, were significantly decreased in amplitude during capsaicin application and after capsaicin removal. Moreover, the topography of these potentials was modified after capsaicin removal, shifting from the central toward the parietal region. Dipolar modelling showed that the dipolar source in the anterior cingulate cortex moved backward after capsaicin removal. All these changes were not observed after stimulation of the left hand, contralateral to the application of capsaicin, thus suggesting that functional changes are selective for the painful skin and the adjacent territories. CONCLUSIONS Our results suggest that acute cutaneous pain may inhibit the neural activity in regions of central nervous system processing nociceptive inputs and cortical representation of these inputs can be rapidly modified in presence of acute pain.

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.