Song-Chou Hsieh

Influence of aging on thermal and vibratory thresholds of quantitative sensory testing

Abstractu2003 Quantitative sensory testing has become a common approach to evaluate thermal and vibratory thresholds in various types of neuropathies. To understand the effect of aging on sensory perception, we measured warm, cold, and vibratory thresholds by performing quantitative sensory testing on a population of 484 normal subjects (175 males and 309 females), aged 48.61u2003±u200314.10 (range 20–86) years. Sensory thresholds of the hand and foot were measured with two algorithms: the method of limits (Limits) and the method of level (Level). Thresholds measured by Limits are reaction‐time‐dependent, while those measured by Level are independent of reaction time. In addition, we explored (1) the correlations of thresholds between these two algorithms, (2) the effect of age on differences in thresholds between algorithms, and (3) differences in sensory thresholds between the two test sites. Age was consistently and significantly correlated with sensory thresholds of all tested modalities measured by both algorithms on multivariate regression analysis compared with other factors, including gender, body height, body weight, and body mass index. When thresholds were plotted against age, slopes differed between sensory thresholds of the hand and those of the foot: for the foot, slopes were steeper compared with those for the hand for each sensory modality. Sensory thresholds of both test sites measured by Level were highly correlated with those measured by Limits, and thresholds measured by Limits were higher than those measured by Level. Differences in sensory thresholds between the two algorithms were also correlated with age: thresholds of the foot were higher than those of the hand for each sensory modality. This difference in thresholds (measured with both Level and Limits) between the hand and foot was also correlated with age. These findings suggest that age is the most significant factor in determining sensory thresholds compared with the other factors of gender and anthropometric parameters, and this provides a foundation for investigating the neurobiologic significance of aging on the processing of sensory stimuli.

Patterns of contact heat evoked potentials (CHEP) in neuropathy with skin denervation: Correlation of CHEP amplitude with intraepidermal nerve fiber density

OBJECTIVEnContact heat evoked potentials (CHEPs) provide an objective approach to investigate cerebral responses to thermal stimuli mediated by Adelta fibers. Skin denervation is often associated with reduced thermal sensibilities. We aimed to investigate the influences of skin denervation on CHEPs in neuropathic patients.nnnMETHODSnCHEPs were recorded at the vertex area by applying contact heat stimuli of 51 degrees C on the distal leg of neuropathic patients with sensory symptoms and pathological evidence of skin denervation in the distal leg. Patterns and parameters of CHEPs in the neuropathic group were compared with those in the control group of age- and gender-matched subjects.nnnRESULTSnThere were 25 neuropathic patients with reduced intraepidermal fiber (IENF) density (1.46+/-1.70fibers/mm, range: 0-5.32). In the control group, well-defined averaged tracings of CHEPs with an initial negative peak (N-wave) followed by a positive peak (P-wave) were consistently recorded in all 25 subjects. The peripheral conduction velocities of CHEPs were 9.92+/-4.06m/s (range: 6.06-16.60), in the range of Adelta fibers. The group of neuropathic patients had markedly reduced N-P amplitudes (p<0.0001) and prolonged N-wave latencies (p=0.049) compared to the control group. IENF density was the only neuropathic parameter correlated with N-P amplitude on multiple linear regression analysis (p=0.010) compared to large-fiber parameters.nnnCONCLUSIONSnIn neuropathic patients with pathological evidence of skin denervation, there were reduced amplitude and prolonged latencies in CHEPs mediated by Adelta fibers. The reduction of CHEP amplitude corresponded to the degree of skin denervation.nnnSIGNIFICANCEnCHEP offers electrophysiological evidence of thermal responses and provides an objective, non-invasive approach to assess the physiological counterparts of skin denervation in neuropathic patients.

Pathophysiology of Neuropathic Pain in Type 2 Diabetes: Skin denervation and contact heat–evoked potentials

OBJECTIVE Neuropathic pain due to small-fiber sensory neuropathy in type 2 diabetes can be diagnosed by skin biopsy with quantification of intra-epidermal nerve fiber (IENF) density. There is, however, a lack of noninvasive physiological assessment. Contact heat–evoked potential (CHEP) is a newly developed approach to record cerebral responses of Aδ fiber–mediated thermonociceptive stimuli. We investigated the diagnostic role of CHEP. RESEARCH DESIGN AND METHODS From 2006 to 2009, there were 32 type 2 diabetic patients (20 males and 12 females, aged 51.63 ± 10.93 years) with skin denervation and neuropathic pain. CHEPs were recorded with heat stimulations at the distal leg, where skin biopsy was performed. RESULTS CHEP amplitude was reduced in patients compared with age- and sex-matched control subjects (14.8 ± 15.6 vs. 33.7 ± 10.1 μV, P < 0.001). Abnormal CHEP patterns (reduced amplitude or prolonged latency) were noted in 81.3% of these patients. The CHEP amplitude was the most significant parameter correlated with IENF density (P = 0.003) and pain perception to contact heat stimuli (P = 0.019) on multiple linear regression models. An excitability index was derived by calculating the ratio of the CHEP amplitude over the IENF density. This excitability index was higher in diabetic patients than in control subjects (P = 0.023), indicating enhanced brain activities in neuropathic pain. Among different neuropathic pain symptoms, the subgroup with evoked pain had higher CHEP amplitudes than the subgroup without evoked pain (P = 0.011). CONCLUSIONS CHEP offers a noninvasive approach to evaluate the degeneration of thermonociceptive nerves in diabetic neuropathy by providing physiological correlates of skin denervation and neuropathic pain.

Glycemic control is related to the severity of impaired thermal sensations in type 2 diabetes

Small‐fibre sensory neuropathy of diabetes presenting as impaired thermal sensations is associated with ominous consequences, such as foot ulcer and amputation, but there is a lack of systematic studies on its occurrence in large cohorts. We investigated (1) the impact of glycemic control on thermal thresholds, (2) the frequencies and patterns of sensory deficits, and (3) the contribution of sensory nerve abnormalities to neuropathic symptoms.

Cutaneous and sympathetic denervation in neonatal rats with a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 gene.

The mutilated-foot rat (mf rat) is an autosomal recessive mutant with characteristic digit deformities in adult animals, and this phenotype mimics many aspects of human sensory neuropathy. The genetics of mf rats was recently elucidated. To understand whether the genotype is responsible for cutaneous denervation before clinically overt mutilation in adult mf rats, we investigated skin innervation in postnatal day 7 (P7) mf rats and compared the patterns with P7 wild-type rats. The mf rat carries a G-->A mutation in the gene encoding the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4). In the footpad skin of P7 mf rats, there was a >90% loss of epidermal nerves (0.7-7.9% of P7 wild-type rats) as indicated by neuronal markers including protein gene product 9.5 (PGP 9.5), growth-associated protein 43 (GAP43), calcitonin gene-related peptide (CGRP), and substance P (SP). The epidermis of hairy skin in hind feet was completely denervated in mf rats as well. Compared with an approximately 80% reduction in the size of dermal nerve fascicles and a parallel loss of nerve fibers, the nearly complete absence of epidermal innervation suggests further sensory nerve degeneration at the level of nerve terminals in the epidermis. In contrast, the loss of epidermal nerves in the abdominal skin of mf rats was less extensive than that in the footpad skin of mf rats; CGRP (+) and SP (+) fibers were moderately reduced (28.3-56.4% of levels of wild-type rats) with normal amounts of PGP 9.5 (+) and GAP43 (+) nerves. Sympathetic innervation as assessed by tyrosine hydroxylase immunoreactivity was absent from the footpad and abdominal skin of mf rats. In conclusion, there is regional skin denervation with diffuse sympathetic denervation in P7 mf rats. These results suggest that the mutation in Cct4 underlies cutaneous nerve degeneration in mf rats.

P063 Disinhibition of motor cortex in post-stroke paresthesia

Pain or paresthesia is one of the major symptoms after stroke. Nonpharmacological treatments including motor cortex electric stimulation or repetitive transcranial magnetic stimulation have been applied to treat such symptoms. However, the underlying pathomechnism of post-stroke pain/paresthesia, especially the excitability of motor cortex, has not been fully elucidated. Here we enrolled thirteen patients (11 men, age 58.8xa0±xa09.0xa0years-old) with persistent post-stroke paresthesia or pain but without motor weakness in the contralateral limbs (durationxa0=xa04.0xa0±xa04.9xa0years). The locations of stroke were pontine, lateral medulla or thalamus. We investigated the short-interval intracortical inhibition and the intracortical facilitation of the motor cortex in the stroke and healthy side of each patient. Paired stimuli of short (3, 5 and 7xa0ms) and medium (10, 15 and 20xa0ms) interstimulus intervals (ISI) were pseudo-randomly mixed with a single stimulus. The motor evoked potentials were recorded from the first dorsal interosseous muscle. There was no difference in the rest motor threshold ( p xa0=xa00.72). The intracortical inhibition at ISI of 3xa0ms were absent ( p xa0=xa00.045), and there was significant facilitation at ISI of 5, 7, 10, 15, 20xa0ms in stroke side ( p p p xa0=xa00.087) and a trend of facilitation at ISI of 10 and 15xa0ms ( p xa0=xa00.057 and 0.077 respectively) in the healthy side. These findings suggested impairment of intracortical inhibition in the motor cortex of stroke side in patients with post-stroke paresthesia or pain.

P14-19 Pathophysiology of painful neuropathy: correlations of contact heat evoked potential with skin innervation

Methods: Subjective assessment comprised of the real-time visual analog scale (RT-VAS) while objective assessment cooperating both skin conductance (SC) and heart rate (HR). Results: Our results indicates a disparity in both subjective and objective assessment on direct comparison of placebo vs. non placebo effects on 20 min of whether anticipation of pain and pain. As compared to the nonplacebo group, the placebo intervention effected a reduction in the both subjective and objective measures after sustained 20 min pain. Significant placebo-induced number of fluctuations in the SC (NFSC) reduction was positively correlated with RT-VAS reduction during pain. HR was significantly decreased for the entire 20 min whereas NFSC was decreased only at first 5 and 10 min during anticipation of pain with placebo compared to only anticipation of pain condition. In the grouped high, middle, low and non responder to placebo analgesic effects, both analgesic efficacy of placebo and placebo-induced NFSC reduction was significantly greater in the high responder compared to non responder during pain. Conclusions: These data demonstrated the utility of both subjective and objective measurement in the determination of the analgesic potential placebo can be assessed by subjective measurement of RT-VAS and objective monitoring of SC and HR. In compared to HR, NFSC is more efficient to evaluate objective assessment in placebo analgesic response and have significant correlation with subjective assessment RT-VAS.

P18-16 Unique spatial patterns of cerebral activations to innocuous versus noxious heat on functional magnetic resonance imaging

Methods: In this fMRI study 15 healthy, left-handed subjects (28.9±9.6 years) and 11 healthy right-handed subjects (35.5±8.6 years) performed bimanual index finger abductions and adductions. In a 2x3 paradigm, subjects had to move their index fingers either in symmetric or in parallel mode in a congruous position, i.e. both palms down, and in two incongruous positions, i.e. either the left or right palm up, respectively. fMRI data were analysed with general linear model (random effects analysis) in an omnibus statistics and with small volume correction based on the main movement effect of all six conditions in comparison with rest. Significant signal changes had a false discovery rate (FDR) <0.05 exceeding clusters of 50 activated voxels. Results: In the incongruous conditions compared with the congruous condition, there was an fMRI-signal increase in a bilateral fronto-parietal network involving motor, premotor somatosensory, and inferior parietal cortical areas. Whereas turning the right hand evoked a predominantly contralateral pattern in right-handers, activations were more bilaterally in the left-handers. In addition, the occipito-temporal cortex probably corresponding to human visual area MT was activated bilaterally in the left-handers. The activation of area MT was specific for the incongruouscongruous contrast in the left-handers but detectable in comparison with rest also in the right-handers. Conclusion: Our observations show extra-activations in sensorimotor control areas during a perceptual dissociation in rightand left-handers. In addition, our data suggest an involvement of visual imagery in the sensory guidance of bimanual coordination in left-handers.

P30.12 Physiological analysis of pain perception by contact heat evoked potential: Effects of aging and gender

yet. Aim: In this study, our aim was to reveal these effects to investigate whether the change of stimulus frequencies could be of convenient use in obtaining more accurate CCT estimations in SEP studies of these patients. Patients and methods: We performed median SEPs of 14 patients with NB and 15 healthy volunteers. We changed the stimulus frequency as 2 Hz, 4 Hz, 6 Hz and 9 Hz in successive recordings and compared the changes on SEP potentials and peak and onset CCT in the Neuro-Behcet (NB) group and the normal group statistically. Results: Our results indicated that the onset CCT values of the NB group were higher than the normal group in 4 Hz and 9 Hz stimulations. However, the comparison of peak CCT in the NB group and the normal group did not show any statistically meaningful differences in all stimulation frequencies. Conclusion: Onset CCT has not been measured before in former SEP studies of patients with NB. We highly recommend measuring onset CCT at higher stimulation frequencies in order to reveal central conduction time pathologies in these patients.