EFFECTS OF AGING ON LASER EVOKED POTENTIALS CHRISTELLE CREAC’H, MD,1,2 ALEXANDRE BERTHOLON,1 PHILIPPE CONVERS, MD,2 LUIS GARCIA-LARREA, MD, PhD,3 and ROLAND PEYRON, MD, PhD1,2 1 Pain Center & Department of Neurology, CHU Saint-Etienne, 42055 Saint-Etienne, France 2 Central Integration of Pain Lab, INSERM U1028 &UMR 5292, Centre for Neuroscience of Lyon, University Claude Bernard of Lyon & University Jean Monnet, 42023 Saint-Etienne, France 3 Central Integration of Pain Lab, INSERM U1028 &UMR 5292, Centre for Neuroscience of Lyon, University Claude Bernard of Lyon, 69003 Lyon, France Accepted 9 September 2014 ABSTRACT: Introduction: Aging has been reported to reduce the amplitude of laser evoked potentials. However, it is unknown whether this effect depends on the length of the sensory fibers. This is an important issue, because most painful neuropathies are length-dependent. Methods: We conducted a study of 40 healthy subjects, half of whom were older than age 50 years. Nociceptive stimuli were delivered to the feet and thighs using a CO2 laser stimulator. Results: Detection and pain perception thresholds did not correlate with age. Latencies of N1, N2, and P2 correlated positively with age on the feet but not on the thighs, whereas the amplitude of N2-P2 decreased with age for both areas. Conclusions: The effects of aging on latencies may reflect a distal loss of peripheral inputs and a length-dependent de-synchronization of the ascending nociceptive volley. Additional changes in peripheral and central processes may explain the diffuse decrease of N2-P2 amplitudes observed with aging. Muscle Nerve 51: 736–742, 2015
Laser stimuli selectively activate Ad and C thermonociceptors in the skin. Recording the brain’s response to these short laser pulses (laser evoked potentials, LEPs) is considered a useful tool for evaluating transmission along small-diameter sensory fibers and investigating the function of spinothalamic pathways.1,2 The first negative component of the response (N1) is observed mainly in the temporal electrodes contralateral to the stimuli. This is thought to be generated in the somatosensory cortex contralateral to the stimuli. The later widespread negative-positive complex N2P2 is assumed to be generated in the operculo-insular cortices and the mid-anterior cingulate cortex.3 In the last decade, LEPs have been shown to detect peripheral and central nervous system lesions affecting the pain / temperature pathways.4–6 However, the vast majority of LEP studies have concentrated exclusively on young or middle-aged subjects, and therefore the sensitivity of LEPs for detecting small-fiber dysfunction in the elderly
Abbreviations: CHEPs, contact-heat evoked potentials; DT, detection threshold; IENF, intra-epidermal nerve fibers; LEPs, laser evoked potentials; NT, nociceptive threshold. Key words: aging; elderly; heat pain; laser evoked potentials; LEPs; nociceptive thresholds ac’h, Ho ^pital Nord, Centre d’Evaluation et Correspondence to: C. Cre Traitement de la Douleur du CHU de Saint-Etienne 42055 Saint-Etienne, cedex 2, France; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 11 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24458
736
remains unknown. While age-related loss of large myelinated fibers is well documented,7 pathological data on small nerve fibers are more inconsistent.8 Aging has been reported to reduce the amplitude of N2P29–11 or even to suppress LEPs in some healthy elderly subjects.12 Abolition of N1 has also been reported with aging,13 but it remains unknown whether the effects of aging on LEPs are dependent on fiber length. This is an important issue in clinical practice, because most painful sensory neuropathies and especially small-fiber neuropathies are known to be length-dependent.14 Age-related length-dependent processes have been shown with skin biopsy15 but not with LEPs. In addition, the prevalence of painful sensory neuropathies increases with age, reaching 2.4–8% in subjects over 55 years.16 The 4week prevalence of any pain was reported to reach 72% in adults aged 50 years and older.17 To improve the reliability of LEPs as a diagnostic tool for all ages, we recorded them in 40 healthy subjects with ages spanning 5 decades, but half were over age 50. The effects of aging were assessed after CO2-laser stimulation of both proximal and distal sites of the lower limbs by investigating detection and nociceptive thresholds, latencies, and amplitudes of LEPs. METHODS
Forty healthy subjects were included in the study (gender ratio 5 1.0; age range, 20–68 years). They were separated into 2 groups (Groups I and II), composed respectively of subjects under and over age 50 years. The cutoff age was set to 50 years, because in our previously unpublished database of 380 patients referred to our laboratory for LEPs with a suspicion of neuropathic pain, the mean age was 50 years. All participants were screened for exclusion criteria that could impair pain perception and/or verbal pain reporting (i.e., ongoing psychotropic or analgesic medication, pain, pregnancy, peripheral neuropathy or neurological disease, diabetes mellitus, or cognitive impairment). The study design was approved by the local Ethics Committee (Saint-Etienne, n 0701035), and informed consent was obtained from all participants. Subjects.
MUSCLE & NERVE
May 2015
Laser Stimulation, Psychophysical Data, and LEPs
A CO2 laser stimulator (Synrad, R , laser wave length 10.6 mm, beam diamOPTILASV eter 1.4 mm, output power 0.3 W) delivered the pulses with a beam using a newly developed chalchogenic infrared fiber. With a fixed output, intensity variations were accomplished by varying the duration of the pulse. The highest laser stimulus intensity delivered during the experiment was 0.3W 3 0.110 s 5 0.033 J, which yielded an average energy density of 21.4 mJ/mm2. We had previously established that this amount of energy did not cause persistent pain or skin irritation. In addition, to minimize sensitization and receptor habituation phenomena, the laser beam was repositioned systematically on a delineated surface area of 4 cm2. Before determining the detection threshold (DT), a few stimuli at a moderate energy density of 7.9 mJ/mm2 were applied as starting point to focus the attention of subjects on the stimulation site. We then delivered a minimal energy of 1 mJ/ mm2 and increased intensities with large steps of 1mJ/ mm2. As soon as the patient felt a sensation, we delivered 3 series of stimuli at decreasing and increasing intensities, with smaller steps to 0.2 mJ/ mm2. The DT was defined as the lowest intensity at which the subjects perceived at least 50% of the stimuli.18 The same method was used to estimate nociceptive thresholds (NT). Laser pulses were applied in random order to the hairy skin on the dorsum of the foot (L5 dermatome) or to the hairy skin on the inferior third of the anterior part on the thigh (L3 dermatome). The order of stimulation (right–left or left–right) was also randomized. During the experiment, the volunteers sat in a comfortable, relaxed position with their eyes open. Skin temperature on the feet was controlled; they were warmed if the skin temperature fell below 29 C. The hair was shaved locally so that it would not affect laser stimulation. To stabilize the attention level across the whole experiment, subjects were instructed to mentally count the number of laser stimuli received. During LEP recordings, the stimulus intensity was set to twice the highest NT (without exceeding 21.4 mJ/mm2), with a mean stimulation frequency of around 0.2 HZ. At the start of LEP recording, if we noticed that the intensity was insufficient to elicit an LEP, we increased the stimulus intensity by adding steps of energy of 1.95 mJ/mm2. We applied this same density of energy in all the following stimulated areas. LEPs were averaged on-line over 2 sets of 10 stimulus repetitions, but we allowed the use of 5 additional laser stimulations if needed (for example when an artifact occurred at the end of the set, or when LEP signals were not steady). We recorded EEG signals with a 21-channel helmet positioned Recording.
according to the 10–20 international system (impedance
Laser stimuli selectively activate Ad and C thermonociceptors in the skin. Recording the brain’s response to these short laser pulses (laser evoked potentials, LEPs) is considered a useful tool for evaluating transmission along small-diameter sensory fibers and investigating the function of spinothalamic pathways.1,2 The first negative component of the response (N1) is observed mainly in the temporal electrodes contralateral to the stimuli. This is thought to be generated in the somatosensory cortex contralateral to the stimuli. The later widespread negative-positive complex N2P2 is assumed to be generated in the operculo-insular cortices and the mid-anterior cingulate cortex.3 In the last decade, LEPs have been shown to detect peripheral and central nervous system lesions affecting the pain / temperature pathways.4–6 However, the vast majority of LEP studies have concentrated exclusively on young or middle-aged subjects, and therefore the sensitivity of LEPs for detecting small-fiber dysfunction in the elderly
Abbreviations: CHEPs, contact-heat evoked potentials; DT, detection threshold; IENF, intra-epidermal nerve fibers; LEPs, laser evoked potentials; NT, nociceptive threshold. Key words: aging; elderly; heat pain; laser evoked potentials; LEPs; nociceptive thresholds ac’h, Ho ^pital Nord, Centre d’Evaluation et Correspondence to: C. Cre Traitement de la Douleur du CHU de Saint-Etienne 42055 Saint-Etienne, cedex 2, France; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 11 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24458
736
remains unknown. While age-related loss of large myelinated fibers is well documented,7 pathological data on small nerve fibers are more inconsistent.8 Aging has been reported to reduce the amplitude of N2P29–11 or even to suppress LEPs in some healthy elderly subjects.12 Abolition of N1 has also been reported with aging,13 but it remains unknown whether the effects of aging on LEPs are dependent on fiber length. This is an important issue in clinical practice, because most painful sensory neuropathies and especially small-fiber neuropathies are known to be length-dependent.14 Age-related length-dependent processes have been shown with skin biopsy15 but not with LEPs. In addition, the prevalence of painful sensory neuropathies increases with age, reaching 2.4–8% in subjects over 55 years.16 The 4week prevalence of any pain was reported to reach 72% in adults aged 50 years and older.17 To improve the reliability of LEPs as a diagnostic tool for all ages, we recorded them in 40 healthy subjects with ages spanning 5 decades, but half were over age 50. The effects of aging were assessed after CO2-laser stimulation of both proximal and distal sites of the lower limbs by investigating detection and nociceptive thresholds, latencies, and amplitudes of LEPs. METHODS
Forty healthy subjects were included in the study (gender ratio 5 1.0; age range, 20–68 years). They were separated into 2 groups (Groups I and II), composed respectively of subjects under and over age 50 years. The cutoff age was set to 50 years, because in our previously unpublished database of 380 patients referred to our laboratory for LEPs with a suspicion of neuropathic pain, the mean age was 50 years. All participants were screened for exclusion criteria that could impair pain perception and/or verbal pain reporting (i.e., ongoing psychotropic or analgesic medication, pain, pregnancy, peripheral neuropathy or neurological disease, diabetes mellitus, or cognitive impairment). The study design was approved by the local Ethics Committee (Saint-Etienne, n 0701035), and informed consent was obtained from all participants. Subjects.
MUSCLE & NERVE
May 2015
Laser Stimulation, Psychophysical Data, and LEPs
A CO2 laser stimulator (Synrad, R , laser wave length 10.6 mm, beam diamOPTILASV eter 1.4 mm, output power 0.3 W) delivered the pulses with a beam using a newly developed chalchogenic infrared fiber. With a fixed output, intensity variations were accomplished by varying the duration of the pulse. The highest laser stimulus intensity delivered during the experiment was 0.3W 3 0.110 s 5 0.033 J, which yielded an average energy density of 21.4 mJ/mm2. We had previously established that this amount of energy did not cause persistent pain or skin irritation. In addition, to minimize sensitization and receptor habituation phenomena, the laser beam was repositioned systematically on a delineated surface area of 4 cm2. Before determining the detection threshold (DT), a few stimuli at a moderate energy density of 7.9 mJ/mm2 were applied as starting point to focus the attention of subjects on the stimulation site. We then delivered a minimal energy of 1 mJ/ mm2 and increased intensities with large steps of 1mJ/ mm2. As soon as the patient felt a sensation, we delivered 3 series of stimuli at decreasing and increasing intensities, with smaller steps to 0.2 mJ/ mm2. The DT was defined as the lowest intensity at which the subjects perceived at least 50% of the stimuli.18 The same method was used to estimate nociceptive thresholds (NT). Laser pulses were applied in random order to the hairy skin on the dorsum of the foot (L5 dermatome) or to the hairy skin on the inferior third of the anterior part on the thigh (L3 dermatome). The order of stimulation (right–left or left–right) was also randomized. During the experiment, the volunteers sat in a comfortable, relaxed position with their eyes open. Skin temperature on the feet was controlled; they were warmed if the skin temperature fell below 29 C. The hair was shaved locally so that it would not affect laser stimulation. To stabilize the attention level across the whole experiment, subjects were instructed to mentally count the number of laser stimuli received. During LEP recordings, the stimulus intensity was set to twice the highest NT (without exceeding 21.4 mJ/mm2), with a mean stimulation frequency of around 0.2 HZ. At the start of LEP recording, if we noticed that the intensity was insufficient to elicit an LEP, we increased the stimulus intensity by adding steps of energy of 1.95 mJ/mm2. We applied this same density of energy in all the following stimulated areas. LEPs were averaged on-line over 2 sets of 10 stimulus repetitions, but we allowed the use of 5 additional laser stimulations if needed (for example when an artifact occurred at the end of the set, or when LEP signals were not steady). We recorded EEG signals with a 21-channel helmet positioned Recording.
according to the 10–20 international system (impedance
