Peripheral and Central Mechanisms of Thermal and Pain Processing in Healthy Human and Neuropathy
Date Issued
2010
Date
2010
Author(s)
Tseng, Ming-Tsung
Abstract
One of the most popular reasons that people come to the hospital for help is the symptoms caused by abnormal somatosensation, particularly pain. Many pain syndromes, particularly neuropathic pain, are usually refractory to medical treatment, which affect the psychophysical well-beings and become a burden on social economics. However, the incomplete understanding about the peripheral and central mechanisms of somatosensory processing impedes the development of new therapeutic strategies. By applying the punch skin biopsy technique with quantification of the intraepidermal nerve fibre (IENF) density to investigate the peripheral nervous system and functional MRI in the central nervous system (CNS), we aim to clarify the mechanisms of thermal and pain processing in healthy human and neuropathy.
The purpose in the first part of our study is (1) to investigate the role of the IENF in the processing of somatosensation in the peripheral nervous system, and (2) to understand the clinical significance and mechanisms of cutaneous denervation in systemic lupus erythematosus (SLE). We assessed IENF density of the distal leg in 45 SLE patients (4 males and 41 females, aged 38.4 ± 13.6 years) and analysed its correlations with pathology, lupus activity, sensory thresholds and electrophysiological parameters. Compared with age- and gender-matched control subjects, SLE patients had lower IENF densities (3.08 ± 2.17 versus 11.27 ± 3.96 fibres/mm, P < 0.0001); IENF densities were reduced in 38 patients (82.2%). Pathologically, 11 patients (24.4%) were found to have definite cutaneous vasculitis; the severity and extent of cutaneous vasculitis were correlated with IENF densities. Patients with active lupus had even lower IENF densities than those with quiescent lupus (1.86 ± 1.37 versus 4.15 ± 2.20 fibres/mm, P = 0.0002). By linear regression analysis, IENF densities were negatively correlated with the SLE disease activity index (r = 0.527, P = 0.0002) and cumulative episodes of lupus flare-up within 2 years before the skin biopsy(r = 0.616, P = 0.0014). Clinically, skin denervation was present not only in the patients with sensory neuropathy but also in the patients with neuropsychiatric syndrome involving the CNS. SLE patients had significantly elevated warm threshold temperatures (P = 0.003) and reduced cold threshold temperatures (P = 0.048); elevated warm threshold temperatures were associated with the reduced IENF densities (P = 0.032).
Taken together, we provide several lines of evidence that IENF reflects thermal and pain sensation, and skin biopsy with quantification of the IENF density was proved as a objective tool to evaluate temperature sensation in the peripheral nervous system. Cutaneous vasculitis and lupus activities underlie skin denervation with associated elevation of thermal thresholds as a major manifestation of sensory nerve injury in SLE.
The aim in the second part of our study is to understand the response patterns to innocuous heat (IH) and noxious heat (NH) in the brain. Whether IH-exclusive brain regions exist and whether patterns of cerebral responses to IH and NH stimulations are similar remain elusive. We hypothesized that distinct and shared cerebral networks were evoked by each type of stimulus. Twelve normal subjects participated in a functional MRI study with rapidly ramped (up to 20 °C/sec) IH (38 °C) and NH (44 °C) applied to the right foot. Group activation maps demonstrated 3 patterns of cerebral activation: (1) IH-responsive only in the inferior parietal lobule (IPL); (2) NH-responsive only in the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), posterior insular cortex (IC), and premotor area (PMA); and (3) both IH- and NH-responsive in the middle frontal gyrus (MFG), inferior frontal gyrus (IFG), anterior IC, cerebellum, superior frontal gyrus, supplementary motor area, thalamus, anterior cingulate cortex (ACC), lentiform nucleus (LN), and midbrain. According to the temporal analysis of regions of interest, the IPL exclusively responded to IH, and the S2, posterior IC, and PMA were exclusively activated by NH throughout the entire period of stimulation. The IFG, thalamus, ACC, and LN responded differently during different phases of IH versus NH stimulation, and the NH-responsive-only S1 responded transiently during the early phase of IH stimulation. BOLD signals in bilateral IPLs were specifically correlated with the ratings of IH sensation, while responses in the contralateral S1 and S2 were correlated with pain intensity. In conclusion, these results suggest that unique brain areas process IH and NH differently in terms of activation location, response intensity, and phase of stimulation.
Subjects
skin innervations
contact heat-evoked potential
functional magnetic resonance imaging
inferior parietal lobule
heat
pain
SDGs
Type
thesis
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