Laser-evoked Responses Research Articles

YAP Ultralate Laser-Evoked Responses in Fibromyalgia: A Pilot Study in Patients with Small Fiber Pathology.

Background: The investigation of C-fiber-evoked ultralow-level responses (ULEPs) at somatic sites is difficult in clinical practice but may be useful in patients with small fiber neuropathy. Aim: The aim of the study was to investigate changes in LEPs and ULEPs in patients with fibromyalgia affected or not by abnormal intraepidermal innervation. Methods: We recorded LEPs and ULEPs of the hand, thigh and foot in 13 FM patients with a normal skin biopsy (NFM), 13 patients with a reduced intraepidermal nerve fiber density (IENFD) (AFM) and 13 age-matched controls. We used a YAP laser, changing the energy and spot size at the pain threshold for LEPs and at the heat threshold for ULEPs. Results: ULEPs occurred at a small number of sites in both the NFM and AFM groups compared to control subjects. The absence of ULEPs during foot stimulation was characteristic of AFM patients. The amplitude of LEPs and ULEPs was reduced in patients with AFM at the three stimulation sites, and a slight reduction was also observed in the NFM group. Conclusions: The present preliminary results confirmed the reliability of LEPs in detecting small fiber impairments. The complete absence of ULEPs in the upper and lower limbs, including the distal areas, could confirm the results of LEPs in patients with small fiber impairments. Further prospective studies in larger case series could confirm the present findings on the sensitivity of LEP amplitude and ULEP imaging in detecting small fiber impairments and the development of IENFD in FM patients.

Cold-evoked potentials in clinical practice: A head-to-head contrast with laser-evoked responses.

Innocuous cooling of the skin activates cold-specific Aδ fibres, and hence, the recording of cold-evoked potentials (CEPs) may improve the objective assessment of human thermo-nociceptive function. While the feasibility of CEP recordings in healthy humans has been reported, their reliability and diagnostic use in clinical conditions have not been documented. Here, we report the results of CEP recordings in 60 consecutive patients with suspected neuropathic pain, compared with laser-evoked potentials (LEPs) which are the gold standard for thermo-algesic instrumental assessment. CEP recording was a well-tolerated procedure, with only ~15 min of surplus in exam duration. The reproducibility and signal-to-noise ratio of CEPs were lower than those of LEPs, in particular for distal lower limbs (LLs). While laser responses were interpretable in all patients, CEPs interpretation was inconclusive in 5/60 because of artefacts or lack of response on the unaffected side. Both techniques yielded concordant results in 73% of the patients. In 12 patients, CEPs yielded abnormal values while LEPs remained within normal limits; 3 of these patients had clinical symptoms limited to cold sensations, including cold-heat transformation. CEPs appear as a useful technique for exploring pain/temperature systems. Advantages are low cost of equipment and innocuity. Disadvantages are low signal-to-noise ratio for LL stimulation, and sensitivity to fatigue/habituation. Joint recording of CEPs and LEPs can increase the sensitivity of neurophysiological techniques to thin fibre- spinothalamic lesions, in particular, when abnormalities of cold perception predominate. Recording of cold-evoked potentials is a well-tolerated, inexpensive and easy-to-use procedure that can be helpful in the diagnosis of abnormalities in the thin fibre- spinothalamic pathways. Supplementing LEPs with CEPs allows consolidating the diagnosis and, for some patients suffering from symptoms limited only to cold, CEPs but not LEPs may allow the diagnosis of thin fibre pathology. Optimal CEP recording conditions are important to overcome the low signal-to-noise ratio and habituation phenomena, which are less favourable than with LEPs.

Clinical criteria and diagnostic assessment of fibromyalgia: position statement of the Italian Society of Neurology-Neuropathic Pain Study Group

BackgroundThe role of central and/or peripheral nervous system dysfunction is basically fundamental in fibromyalgia.AimThe aim of this position statement on behalf of the Neuropathic Pain Study Group of the Italian Society of Neurology is to give practical guidelines for the clinical and instrumental assessment of fibromyalgia (FM) in the neurological clinical practice, taking into consideration recent studies.MethodsCriteria for study selection and consideration were original studies, case-controls design, use of standardized methodologies for clinical practice, and FM diagnosis with ACR criteria (2010, 2011, 2016).ResultsACR criteria were revised. For diagnostic procedure of small-fiber pathology, 47 studies were totally considered.Recent diagnostic criteria should be applied (ACR, 2016). A rheumatologic visit seems mandatory. The involvement of small fibers should request at least 2 among HRV + SSR and/or laser-evoked responses and/or skin biopsy and/or corneal confocal microscopy, eventually followed by monitoring of metabolic and/or immunological/ and or/paraneoplastic basis, to be repeated at 1-year follow-up.ConclusionsThe correct diagnostic approach to FM could promote the exclusion of the known causes of small-fiber impairment. The research toward common genetic factors would be useful to promote a more specific therapeutic approach.

N°71 – Cold-evoked potentials in clinical practice: A head-to-head contrast with laser-evoked responses

N°71 – Cold-evoked potentials in clinical practice: A head-to-head contrast with laser-evoked responses

Auditory cortical activity elicited by infrared laser irradiation from the outer ear in Mongolian gerbils.

Infrared neural stimulation has been studied for its potential to replace an electrical stimulation of a cochlear implant. No studies, however, revealed how the technic reliably evoke auditory cortical activities. This research investigated the effects of cochlear laser stimulation from the outer ear on auditory cortex using brain imaging of activity-dependent changes in mitochondrial flavoprotein fluorescence signal. An optic fiber was inserted into the gerbil's ear canal to stimulate the lateral side of the cochlea with an infrared laser. Laser stimulation was found to activate the identified primary auditory cortex. In addition, the temporal profile of the laser-evoked responses was comparable to that of the auditory responses. Our results indicate that infrared laser irradiation from the outer ear has the capacity to evoke, and possibly manipulate, the neural activities of the auditory cortex and may substitute for the present cochlear implants in future.

Non-invasive vagus nerve stimulation: effects on trigeminal laser evoked potentials

A portable transcutaneous non-invasive device that stimulates the cervical portion of the vagus nerve has been developed (GammaCore®) for the treatment of migraine. Cervical nVNS was shown to rapidly inhibit cortical spreading depression in rodents, providing important insights into the mode of action of nVNS. We aimed to test the effects of cervical nVNS on cortical responses and Gamma Band Oscillations (GBO) induced by painful laser stimuli delivered to the right and left forehead and hands in a cohort of twenty-eight migraine patients. Patients were selected and randomly assigned to active or sham nVNS stimulation on the neck bilaterally with GammaCore®. We recorded Laser evoked responses (LEPs) by stimulating bilaterally the hand and the forehead, in basal condition, during nVNS and sham stimulation and two minutes after stimulation. We observed a significant reduction of amplitude of the P2 wave from the forehead during active nVNS, as compared to basal and sham stimulation. However LEPs amplitude immediately recovered after stimulation session. The sham device induced an evident reduction of LEP amplitude, though not significant in respect to active device. Active nVNS seems to have a transitory effect on the transmission of trigeminal pain, which can contribute to induce changes of trigeminal function improving migraine.

Functional Connectivity of EEG Signals Under Laser Stimulation in Migraine.

In previous studies, migraine patients showed abnormalities in pain-related evoked responses, as reduced habituation to repetitive stimulation. In this study, we aimed to apply a novel analysis of EEG bands synchronization and directed dynamical influences under painful stimuli in migraine patients compared to non-migraine healthy volunteers. Thirty-one migraine without aura outpatients (MIGR) were evaluated and compared to 19 controls (CONT). The right hand was stimulated by means of 30 consecutive CO2 laser stimuli. EEG signal was examined by means of Morlet wavelet, synchronization entropy (SE), and Granger causality (GC), and the statistically validated results were mapped on the corresponding scalp locations. The vertex complex of averaged laser-evoked responses (LEPs) showed reduced habituation compared to CONT. In the prestimulus phase, enhanced SE in the 0, 5–30 Hz range was present in MIGR and CONT between the bilateral temporal–parietal and the frontal regions around the midline. Migraine patients showed an anticipation of EEG changes preceding the painful stimulation compared to CONT. In the poststimulus phase, the same cortical areas were more connected in MIGR vs CONT. In both groups of patients and CONT, the habituation index was negatively correlated with the GC scores. A different pattern of cortical activation after painful stimulation was present in migraine. The increase in cortical connections during repetitive painful stimulation may subtend the phenomenon of LEPs reduced habituation. Brain network analysis may give an aid in understanding subtle changes of pain processing under laser stimuli in migraine patients.

Migraine and functional connectivity: an innovative pathophysiological perspective.

Migraine is a chronic disorder of neuro-vascular origin, characterized by abnormal neuronal excitability and altered processing of multimodal stimuli. Methods able to detect subtle changes of EEG rhythms under painful stimulation may improve the knowledge of mechanisms of pain processing in normal subjects and patients with chronic pain syndromes. The study of the dynamical relationships between signals recorded at different scalp locations can help to confirm and formulate hypotheses on the physiological mechanisms related to stimuli processing. Correlations, spectral coherence and phase synchronization, which allow to understand the extent to which two variables are statistically connected or shared, influenced by a third variable, together with analyses of the directionality of these dynamical interactions, may potentially contribute to understanding the mechanism of pain processing in migraine. Functional and effective connectivity in terms of synchronization and information transfer were able to reveal differences in visual reactivity between migraine patients and controls, so these methods may presumably outline a different way to process nociceptive laser stimuli in migraine, giving further knowledge on how the cortex changes its inter-connections under painful inputs. Thirty-one migraine without aura outpatients (MwoA) were evaluated and compared to 19 controls (CONT). The right hand was stimulated by means of 30 consecutive CO2 laser stimuli. EEG signal was examined by means of Morlet wavelet, synchronization entropy and Granger causality, and the statistic results embedded into a scalp model. The vertex complex of averaged laser evoked responses (LEPs) showed reduced habituation compared to controls. In the pre-stimulus phase enhanced synchronization entropy in the 0, 5-30 Hz range was present in MwoA and CONT between the bilateral temporal parietal and the frontal regions around the midline. Migraine patients showed an anticipation of EEG changes preceding the painful stimulation compared to controls. In the post-stimulus phase, the same cortical areas were more connected in MwoA vs CONT. In the totality of patients and controls, the habituation index was negatively correlated with the Granger Causality scores. A different pattern of cortical activation after painful stimulation was present in migraine. The increase in cortical connections during repetitive painful stimulation may subtend the phenomenon of LEPs reduced habituation. Brain network analysis may give an aid in understanding subtle changes of pain processing under laser stimuli in migraine patients. Written informed consent to publication was obtained from the patient(s).

Pain in prolonged disorders of consciousness: Laser evoked potentials findings in patients with vegetative and minimally conscious states

Introduction: Pain perception is currently an open question in patients suffering from prolonged disorders of consciousness. The aim of the present study was to examine nociceptive specific laser evoked responses (LEPs) in view of long-latency evoked potentials by non-painful electrical stimuli (SEPs) and auditory mismatch negativity (MM).Methods: Three vegetative state (VS), four minimal Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, stimulating the dorsum of the right hand by noxious laser and innocuous electrical stimulus, according to normal controls subjective rating. An auditory paradigm for MM was also employed.Results: The MM was present in all patients. The LEP vertex complex was recognizable in all cases, with a significant latency increase of both N2 and P2 which displayed changes of topographic representation. Late SEPs were absent in all patients except in one MCS case, who showed a significant N2 and P2 latency increase.Discussion: The results may suggest that high relevant stimuli may be processed even in patients with severe brain damage. Larger series and multimodal approaches may contribute to confirm that cortical arousal toward pain salience may be a primary function for life persistence.

Laser-induced withdrawal test for electrophysiological recordings of nociception

CO(2) lasers are often used in pain research. However, the stimulation parameters of the CO(2) lasers, such as beam diameter, laser power, etc., used for these animal nociceptive studies vary across laboratories. The differences of the parameters usually make novices who want to reproduce the laser-evoked responses confused to follow. In this study, we quantitatively measured the laser-withdrawal reflex of the rat to ascertain the individual laser-withdrawal threshold and then found the thresholds were diverse among the rats we adopted. Furthermore, the optimal stimulation distance, the most conveniently modified stimulation parameter of CO(2) laser stimuli, was also determined. We suggest that laser-withdrawal tests should be applied before the electrophysiological recordings in order to verify the efficiency of the induced nociception and substantiate the operational parameters of the CO(2) laser device.

The time course of CO2 laser-evoked responses and of skin nerve fibre markers after topical capsaicin in human volunteers

To assess the temporal relationship between skin nerve denervation and regeneration (dermal and intra-epidermal fibres, IENF) and functional changes (CO(2) laser-evoked potentials, LEPs, and quantitative sensory tests, QST) after topical cutaneous application of capsaicin. Capsaicin (0.075%) was applied to the lateral calf for three consecutive days. QST, LEPs and skin biopsies were performed at baseline and time intervals up to 54days post-capsaicin treatment. Biopsies were immunostained with antibodies for PGP9.5, TRPV1, and GAP-43 (marker of regenerating nerve fibres), and analyzed for IENFs and dermal innervation (for GAP-43). At 1day post-capsaicin, cutaneous thermal sensitivity was reduced, as were LEPs. PGP9.5, TRPV1, and GAP-43 immunoreactive-nerve fibres were almost completely absent. By Day 12, LEPs had fully recovered, but PGP9.5 and TRPV1 IENF continued to be significantly decreased 54days post-capsaicin. In contrast, dermal GAP-43 immunoreactivity closely matched recovery of LEPs. A good correlation was observed between LEPs and GAP-43 staining, in contrast to PGP9.5 and TRPV1. Laser stimulation is a non-invasive and sensitive method for assessing the initial IENF loss, and regenerating nerve fibres. Assessing skin biopsies by PGP9.5 immunostaining alone may miss significant diagnostic and prognostic information regarding regenerating nerve fibres, if other approaches are neglected, e.g. LEPs or GAP-43 immunostaining.

P060 Reliability of early and late laser-evoked responses

P060 Reliability of early and late laser-evoked responses

Measurement of skin temperature after infrared laser stimulation

Objectives Several types of lasers are available for eliciting laser evoked responses (LEPs). In order to understand advantages and drawbacks of each one, and to use it properly, it is important that the pattern of skin heating is known and duly considered. This study was aimed at assessing the skin temperature during and immediately after irradiation with pulses by Nd:YAP and CO 2 lasers. Materials and Methods The back of the non-dominant hand was irradiated in 8 subjects. Temperatures were measured by a fast analogical pyrometer (5 ms response time). Stimuli were tested on natural colour (white) and blackened skin. Results Nd:YAP pulses yielded temperatures that were correlated with pulse energy, but not with pulse duration; much higher temperatures were obtained irradiating blackened skin than white skin (ranges 100-194 °C vs 35-46 °C). Temperature decay was extremely slow in white skin, reaching its basal value in more than 30 s. CO 2 pulses delivered with power of 3W and 6W yielded temperatures of 69-87 °C on white skin, and 138-226 °C on blackened skin. Temperature decay was very fast (4-8 ms). Conclusions Differences in peak temperatures and decay times between lasers and tested conditions depend on energy and volume of heated skin. The highest temperatures are reached with lesser degree of penetration, as in the case of CO 2 laser and blackened skin. Taking into account the temperature decay time of the skin, the minimum interstimulus interval to get reliable LEPs should be no less than 10 s for Nd:YAP and 100 ms for CO 2 laser. Another important practical consequence of the heating pattern is that the Nd:YAP pulses will activate warmth receptors more easily than CO 2.