Cortical representation of pain in primary sensory‐motor areas (S1/M1)—a study using intracortical recordings in humans

Intracortical evoked potentials to nonnoxious Aβ (electrical) and noxious Aδ (laser) stimuli within the human primary somatosensory (S1) and motor (M1) areas were recorded from 71 electrode sites in 9 epileptic patients. All cortical sites responding to specific noxious inputs also responded to nonnoxious stimuli, while the reverse was not always true. Evoked responses in S1 area 3b were systematic for nonnoxious inputs, but seen in only half of cases after nociceptive stimulation. Nociceptive responses were systematically recorded when electrode tracks reached the crown of the postcentral gyrus, consistent with an origin in somatosensory areas 1–2. Sites in the precentral cortex also exhibited noxious and nonnoxious responses with phase reversals indicating a local origin in area 4 (M1). We conclude that a representation of thermal nociceptive information does exist in human S1, although to a much lesser extent than the nonnociceptive one. Notably, area 3b, which responds massively to nonnoxious Aβ activation was less involved in the processing of noxious heat. S1 and M1 responses to noxious heat occurred at latencies comparable to those observed in the supra‐sylvian opercular region of the same patients, suggesting a parallel, rather than hierarchical, processing of noxious inputs in S1, M1 and opercular cortex. This study provides the first direct evidence for a spinothalamic related input to the motor cortex in humans. Hum Brain Mapp 34:2655–2668, 2013. © 2012 Wiley Periodicals, Inc.     

Sensory deficits of a nerve root lesion can be objectively documented by somatosensory evoked potentials elicited by painful infrared laser stimulations: a case study.

Somatosensory evoked potentials (SEPs) in response to painful laser stimuli were measured in a patient with a unilateral sensory deficit due to radiculopathy at cervical levels C7 and C8. Laser evoked potentials (LEPs) were compared with SEPs using standard electrical stimulation of median and ulnar nerves at the wrist and mechanical stimulation of the fingertips by means of a mechanical stimulator. Early and late ulnar and median nerve SEPs were normal. Mechanical stimulation resulted in w shaped early SEPs from all five fingertips with some degree of abnormality at the fourth and fifth digits of the affected hand. Late LEPs were completely absent for stimulations at affected dermatomes and normal in the unaffected control dermatomes. The border between skin areas with normal or absent LEPs was very sharp and fitted the dermatomes of intact C6 and damaged C7 and C8 nerve roots. It is suggested that pain dermatomes are narrower than tactile dermatomes because thin fibres of the nociceptive system, activated by laser stimuli, probably do not overlap between adjacent spinal segments to the same extent as thick fibres of the mechanoreceptive system, activated by standard electrical or mechanical stimulation.     

Neurophysiological evaluation of sensorimotor functions of the leg: comparison of evoked cortical potentials following electrical and mechanical stimulation,long-latency muscle responses,and transcranial magnetic stimulation

Summary Twenty-two patients with localized lesions of the central nervous system (unilateral cerebral ischaemia, cervical myelopathy, spinal tumour, familial spastic paraplegia) underwent neurophysiological evaluation of sensorimotor deficits of the leg. Functional methods using muscle stretch as stimulus, i.e. long-latency muscle responses and cortical potentials evoked by dorsiflection of the foot, were compared with transcranial magnetic stimulation and somatosensory evoked cortical potentials following electrical stimulation of the posterior tibial nerve. The functional neurophysiological methods yielded no diagnostic superiority with respect to the procedures using artificial (i.e. magnetic and electrical) stimulation. However, in most cases of missing compound motor action potentials following transcranial magnetic stimulation or missing electrically evoked cortical potentials, the long-latency muscle responses still allowed quantitative assessment of sensorimotor function.     

Dermatomal somatosensory evoked potentials of the lumbar and cervical roots

Summary We describe a method for obtaining cortical evoked potentials after stimulation of the lumbosacral and cervical dermatomes in healthy volunteers. Such dermatomal evoked potentials are expected to contribute to the diagnosis of lumbar and cervical root entrapment. Normative data are presented for each dermatome including left-right differences. A significant correlation was found between absolute latencies and body length for the lumbosacral segments. This correlation was virtually absent in the cervical segments. The latency difference between the same cervical or lumbosacral dermatome left and right was also independent of body length for all segments.     

Increased baseline temperature improves the acquisition of contact heat evoked potentials after spinal cord injury

ObjectiveTo investigate the effect of increasing the skin surface baseline temperature for contact heat evoked potentials (CHEPs).MethodsCHEPs were studied in healthy subjects and subjects with chronic cervical spinal cord injury (SCI) using a conventional 35 °C (condition 1) or increased 42–45 °C baseline temperature (condition 2). A third condition was used to standardize the contact heat stimulus duration from the different baseline temperatures. Changes in peak latency and N2P2 amplitude of the CHEPs and rating of perceived intensity were examined between conditions.ResultsIn healthy subjects, increasing the baseline temperature for contact heat stimulation significantly increased the rating of perceived intensity (conditions 2 and 3), as well as the amplitude of CHEPs (condition 2 only). Following SCI, an increased baseline temperature facilitated perception of contact heat stimulation and evoked potentials could be recorded from dermatomes that were insensitive to contact heat from a conventional baseline temperature.ConclusionsEnhancing the acquisition of CHEPs can be achieved by increasing the baseline temperature. This effect can be attributed, in part, to shortening the stimulation duration.SignificanceAfter SCI, increasing the baseline temperature for CHEPs in dermatomes with absent or diminished sensation improved the neurophysiological resolution of afferent sparing.     

The effects of transcranial direct current stimulation on conscious perception of sensory inputs from hand palm and dorsum

Conscious perception of sensory signals depends in part on stimulus salience, relevance and topography. Letting aside differences at skin receptor level and afferent fibres, it is the CNS that makes a contextual selection of relevant sensory inputs. We hypothesized that subjective awareness (AW) of the time at which a sensory stimulus is perceived, a cortical function, may be differently modified by cortical stimulation, according to site and type of the stimulus. In 24 healthy volunteers, we examined the effects of transcranial direct current stimulation (tDCS) on the assessment of AW to heat pain or weak electrical stimuli applied to either the hand palm or dorsum. We also recorded the vertex‐evoked potentials to the same stimuli. The assessment was done before, during and after cathodal or anodal tDCS over the parietal cortex contralateral to the hand receiving the stimuli. At baseline, AW to thermal stimuli was significantly longer for palm than for dorsum (P < 0.01), while no differences between stimulation sites were observed for the electrical stimuli. Both cathodal and anodal tDCS caused a significant shortening of AW to thermal stimuli in the palm but not in the dorsum, and no effects on AW to electrical stimuli. Longer AW in the palm than in the dorsum may be attributable to differences in skin thickness. However, the selectivity of the effects of tDCS on AW to thermal stimulation of the glabrous skin reflects the specificity of CNS processing for site and type of sensory inputs.     

Electrically evoked nociceptive potentials for early detection of diabetic small‐fiber neuropathy

Background and purpose: This study investigated the utility of pain‐related evoked potentials (PREP’s) elicited by a nociceptive electrical stimulation of the skin (= electrically evoked nociceptive potentials) in early detection of diabetic small‐fiber neuropathy. Methods: We studied 36 ‘young’ (19–35 years) and 24 ‘older’ (36–65 years) healthy subjects as well as 35 patients (35–64 years) with diabetes and neuropathic symptoms and 22 patients (34–64 years) with diabetes without neuropathic symptoms. Only patients with normal standard nerve conduction testing were included. Results: In patients with neuropathic symptoms, we found a significant increase in PREP latencies and decrease of amplitudes elicited from both, upper and lower limbs. In non‐symptomatic diabetic patients, we observed PREP abnormalities from lower limbs only. Conclusions: These data suggest that the method of pain‐related evoked potentials elicited by a nociceptive electrical stimulation of the skin may contribute to the early detection of diabetic sensory neuropathy.     

Peripheral Nerve Stimulation Inhibits Nociceptive Processing: An Electrophysiological Study in Healthy Volunteers

Objectives. Electric peripheral nerve stimulation (PNS) is a neuromodulatory therapy in pain patients. The efficacy of this neurosurgical pain treatment is controversial because its antinociceptive effect in humans has not been objectively proven so far. Materials and Methods. Noxious infrared laser stimulation of the left hand dorsum evoked cortical potentials (LEP) by selective excitation of Aδ‐fiber nociceptors in 15 healthy volunteers under control and PNS conditions. LEP were recorded before, during, and after electric Aβ‐fiber stimulation (PNS) of the left superficial radial nerve. In the control session LEP were recorded without PNS. Laser stimulus intensity ratings, LEP latencies, and amplitudes were statistically analyzed (anova ). Results. During PNS, LEP amplitudes (p < 0.001) and laser intensity ratings (p < 0.05) significantly decreased, and LEP latencies significantly increased (p < 0.05). Under control conditions LEP and intensity ratings remained unchanged. Conclusions. The electrophysiologic data provide evidence that electric stimulation of peripheral Aβ‐fibers reliably suppresses Aδ‐fiber nociceptive processing in human volunteers.     

Differential effects of cathodal transcranial direct current stimulation of prefrontal,motor and somatosensory cortices on cortical excitability and pain perception – a double‐blind randomised sham‐controlled study

The primary aim of this study was to assess the effects of cathodal transcranial direct current stimulation (c‐tDCS) over cortical regions of the pain neuromatrix, including the primary motor (M1), sensory (S1) and dorsolateral prefrontal (DLPFC) cortices on M1/S1 excitability, sensory (STh), and pain thresholds (PTh) in healthy adults. The secondary aim was to evaluate the placebo effects of c‐tDCS on induced cortical and behavioural changes. Before, immediately after and 30 min after c‐tDCS the amplitude of N20–P25 components of somatosensory evoked potentials (SEPs) and peak‐to‐peak amplitudes of motor evoked potentials (MEPs) were measured under four different experimental conditions. STh and PTh for peripheral electrical and mechanical stimulation were also evaluated. c‐tDCS of 0.3 mA was applied for 20 min. A blinded assessor evaluated all outcome measures. c‐tDCS of M1, S1 and DLPFC significantly decreased the corticospinal excitability of M1 (P < 0.05) for at least 30 min. Following the application of c‐tDCS over S1, M1 and DLPFC, the amplitude of the N20–P25 component of SEPs decreased for at least 30 min (P < 0.05). Compared with baseline values, significant STh and PTh increases were observed after c‐tDCS of these three sites. Decreasing the level of S1 and M1 excitability, following S1, M1 and DLPFC stimulation, confirmed the functional connectivities between these cortical sites involved in pain processing. Furthermore, increasing the level of STh/PTh after c‐tDCS of these sites indicated that stimulation of not only M1 but also S1 and DLPFC could be considered a technique to decrease the level of pain in patients.     

Intra-epidermal evoked potentials: A promising tool for spinal disorders?

ObjectivesTo test the robustness and signal-to-noise ratio of pain-related evoked potentials following intra-epidermal electrical stimulation (IES) compared to contact heat stimulation in healthy controls, and to explore the feasibility and potential added value of IES in the diagnosis of spinal disorders.MethodsPain-related evoked potentials induced by IES (custom-made, non-invasive, concentric triple pin electrode with steel pins protruding 1 mm from the anode, triangularly separated by 7–10 mm respectively) and contact heat stimulation were compared in 30 healthy subjects. Stimuli were applied to four different body sites. Two IES intensities, i.e., high (individually adapted to contact heat painfulness) and low (1.5 times pain threshold), were used. Additionally, a 40-year-old patient with unilateral dissociated sensory loss due to a multi-segmental syringohydromyelia was assessed comparing IES and contact heat stimulation.ResultsBoth IES and contact heat stimulation led to robust pain-related evoked potentials recorded in all healthy subjects. Low intensity IES evoked potentials (14.1–38.0 µV) had similar amplitudes as contact heat evoked potentials (11.8–32.3 µV), while pain ratings on the numeric rating scale were lower for IES (0.8–2.5, compared to 1.5–3.9 for contact heat stimulation). High intensity IES led to evoked potentials with higher signal-to-noise ratio than low intensity IES and contact heat stimulation. The patient case showed impaired pain-related evoked potentials in segments with hypoalgesia for both IES modes. IES evoked potentials were preserved, with delayed latencies, while contact heat evoked potentials were abolished.ConclusionIES evoked robust pain-related cortical potentials, while being less painful in healthy controls. The improved signal-to-noise ratio supports the use of IES for objective segmental testing of nociceptive processing. This was highlighted in a spinal syndrome case, where IES as well as contact heat stimulation reliably detected impaired segmental nociception.     

Cognitive evoked potentials to anticipated oesophageal stimulus in humans: quantitative assessment of the cognitive aspects of visceral perception

Evoked potential studies provide an objective measure of the neural pathways involved with perception. The effects of cognitive factors, such as anticipation or awareness, on evoked potentials are not known. The aim was to compare the evoked potential response to oesophageal stimulation with the cortical activity associated with anticipation of the same stimulus. In 12 healthy men (23.5 +/- 4 years), oesophageal electrical stimulation (15 mA, 0.2 Hz, 0.2 msec) was applied, and the evoked potentials recorded using scalp electrodes. A computerized model of randomly skipped stimuli (4:1 ratio) was used to separately record the evoked potentials associated with stimulation and those associated with an anticipated stimulus. The electrical stimulus represented the nontarget stimulus and the skipped impulse the target (anticipatory) stimulus. This anticipatory evoked potential was also compared to auditory P300 evoked potentials. Reproducible evoked potentials and auditory P300 responses were elicited in all subjects. Anticipatory evoked potentials (peak latency 282.1 +/- 7.9 msec, amplitude 8.2 +/- 0.7 microV, P < 0.05 vs auditory P300 evoked potential) were obtained with the skipped stimulus. This anticipatory evoked potential was located frontocentrally, while the auditory P300 potential was located in the centro-parietal cortex. The anticipatory evoked potential associated with expectation of an oesophageal stimulus, although of similar latency to that of the auditory P300 evoked response, originates from a different cortical location. The recording of cognitive evoked potentials to an expected oesophageal stimulus depends on attention to, and awareness of, the actual stimulus. Anticipatory evoked potentials to GI stimuli may provide an objective electrophysiological tool for the assessment of the cognitive factors associated with visceral perception.     

Short-latency somatosensory evoked potentials in brain death

Summary Simultaneous recording of somatosensory evoked potentials to median nerve stimulation above the upper and lower neck in brain-dead patients revealed that all cervical responses were preserved in 10%, whereas a marked reduction in amplitude or even loss of N 13b at the level of the C2 spinous process was observed in 90%. Of the patients, 55% revealed an additional loss of N 13a, recorded at the level of the C7 spinous process; in 15% all cortical and spinal evoked potentials were missing, but Erb's point waves were still normal. These results suggest two different origins of the main negative waves (N 13a and N 13b), recorded above the upper and lower cervical spinal cord. N 13a (C7) is supposed to arise in the dorsal horn at the C6/7 level, N 13b (C2) in the cervicomedullary junction.     

Processing of nociceptive input from posterior to anterior insula in humans

Previous brain imaging studies have shown robust activations in the insula during nociceptive stimulation. Most activations involve the posterior insular cortex but they can cover all insular gyri in some fMRI studies. However, little is known about the timing of activations across the different insular sub‐regions. We report on the distribution of intracerebrally recorded nociceptive laser evoked potentials (LEPs) acquired from the full extent of the insula in 44 epileptic patients. Our study shows that both posterior and anterior subdivisions of the insular cortex respond to a nociceptive heat stimulus within a 200–400 ms latency range. This nociceptive cortical potential occurs firstly, and is larger, in the posterior granular insular cortex. The presence of phase reversals in LEP components in both posterior and anterior insular regions suggests activation of distinct, presumably functionally separate, sources in the posterior and anterior parts of the insula. Our results suggest that nociceptive input is first processed in the posterior insula, where it is known to be coded in terms of intensity and anatomical location, and then conveyed to the anterior insula, where the emotional reaction to pain is elaborated. Hum Brain Mapp 35:5486–5499, 2014. © 2014 Wiley Periodicals, Inc.     

Ultralate cerebral potentials as correlates of delayed pain perception: observation in a case of neurosyphilis.

Evoked cerebral potentials were investigated in a patient with neurosyphilis, who showed the symptoms of delayed pain perception in the lower limbs: a pinprick to the legs was perceived with a latency of more than one second. After stimulation with CO2 laser radiant heat pulses, evoked cerebral potentials of upper limbs were observed in a latency range comparable to those of healthy subjects, with a negative peak at 250 ms and a positive peak at 370 ms. In contrast, after application of laser stimuli to body sites with delayed pain perception, latency of the evoked potentials drastically increased with a vertex negativity at 1300 ms and a positivity at 1420 ms. Evoked potential measurements with conventional electrical stimuli did not show any difference between affected and unaffected body sites, that is, stimulation of the affected body sites did not produce pathological potentials.     

Contact heat evoked potentials: Reliable acquisition from lower extremities

Objective

To investigate test-retest reliability of contact heat evoked potentials (CHEPs) from lower extremities using two different stimulation protocols, i.e., normal and increased baseline temperature.

Changes in subcortical visual and auditory evoked potentials following amygdaloid kindling in cats

In this study we dealt with the changes in visual and auditory evoked potentials following kindling, to reveal the distant effects of epileptic activity. The experiments were performed using cats. Visual and auditory evoked potentials were obtained initially. Daily stimulation of 60 Hz (rectangular wave, 1 ms in duration, 500 microA in peak current, 2-s train) was given to the right amygdala, for kindling. After the completion of kindling, evoked responses were recorded again. In the auditory system the changes of responses in the cortex, medial geniculate nucleus, and cochlear nucleus were distinguished. The changes of potentials in the subcortex were larger than those at the cortical level. For visual evoked potentials there was a discrepancy between stimulation with light and electrical stimulation of the optic chiasm. There was no significant change in amplitude of visual evoked potentials by flash. In the case of optic chiasm stimulation, an enlargement of evoked responses was obtained. These results indicate modality-specific change of the auditory system and widespread subcortical change. These results might be caused by some vulnerability of the auditory system in the case of amygdaloid kindling, as a result of the epileptogenic process.     

Fully intact contact heat evoked potentials in patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is typically considered to be a disease of motor, not sensory, neurons. However, reports exist of sensory system involvement in ALS. In this study we aimed to study the characteristic of contact heat‐evoked potentials (CHEPs) in patients with ALS and to evaluate the nociceptive pathway in these patients. Sixty patients with ALS and 60 controls had pain elicited by a CHEP stimulator with an accelerated velocity of 70°C/s. Thermal stimuli were sent at 54.5°C to three body sites: the dorsum of the hand, the proximal volar forearm, and the skin near C7. CHEPs were recorded from Cz and Pz. The onset negative peak latencies were 561.2 ± 28.6 ms, 540.1 ± 39.2 ms, and 502.4 ± 26.2 ms when the dorsum of the hand, the proximal volar forearm, and skin near C7 were stimulated, respectively. There were no significant differences between the ALS patients and the controls with CHEP (P > 0.05). Our results suggest that the nociceptive pathway is intact and support the idea that small fibers and their sensory pathway are spared in ALS. Muscle Nerve, 2009     

Somatosensory evoked potentials from musculocutaneous nerve in the diagnosis of brachial plexus injuries

A technique for recording somatosensory evoked potentials using stimulation of musculocutaneous sensory nerve fibers proximal to the wrist has been used in 10 normal subjects and in 8 patients with traumatic lesions of proximal parts of the brachial plexus. The technique gave satisfactory evoked potentials in all normal subjects and provided useful information in patients with avulsion of the 5th and 6th cervical roots. The results were similar to those obtained by radial nerve stimulation. The results in 3 patients with upper trunk injuries and in 1 patient with avulsion of the 5th cervical root were unhelpful. In 2 patients with multiple cervical root avulsions the evoked potentials from cervical cord and contralateral scalp were absent and were attenuated at Erb's point. This is the first report where musculocutaneous nerve evoked potentials have been applied to a group of patients.     

Laser evoked potentials using the Nd:YAG laser

Pain-related cortical potentials were evoked by skin stimulation of the face and the limbs with 5-ns-duration laser pulses delivered by a Q-switched Nd:YAG laser. Such laser pulses, in the nanosecond range, were able to induce pinprick pain sensations and to evoke reproducible laser evoked potentials (LEPs) without visible skin lesions for an energy density of less than 18 mJ/mm(2). Low energy densities, around 10 mJ/mm(2), were sufficient to reach the pain threshold and to induce LEP. The mean conduction velocity of the stimulated afferent fibers was close to 20 m/s, consistent with the stimulation of Adelta fibers. The amplitude of LEP correlated with pain perception rather than with energy density. The differences, such as wavelength and stimulus duration, between the Q-switched Nd:YAG laser we used and the lasers that are currently used in LEP studies (i.e., CO(2), argon, or Tm:YAG lasers in the millisecond range) are discussed. Our study opens novel perspectives in the LEP field of research by using a new type of laser with a very short pulse duration.     

Spinal components of the cerebral somatosensory evoked response in normal man: The "S wave"

Responses evoked over the scalp and the neck by median nerve (or finger I) stimulation were concurrently recorded in 10 subjects. It was found that the first component of the cortical SEP consists of a small amplitude polyphasic wave (S wave) which could be recorded bilaterally upon unilateral stimulation. The polarity of the S wave varied according to the reference electrode position, at variance with the P₁₅ component which remained constantly positive. It is therefore correct to assume that different generators are responsible for these two potentials.
The synchrony between the S wave and the cervical response, which is largely spinal in origin, as well as some pertinent experimental data, suggest that the S wave is a far field reflection of activity generated mainly in the cervical dorsal columns. These findings might be relevant to the diagnosis of neurological disorders.