Ming-Tsung Tseng

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

OBJECTIVE Contact 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. METHODS CHEPs 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. RESULTS There 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. CONCLUSIONS In 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. SIGNIFICANCE CHEP offers electrophysiological evidence of thermal responses and provides an objective, non-invasive approach to assess the physiological counterparts of skin denervation in neuropathic patients.

Effects of aging on contact heat-evoked potentials: The physiological assessment of thermal perception

Age significantly influences the detection thresholds to noxious heat; such thresholds depend on responses in the cerebral cortex to thermal stimuli and the psychophysical perception of such responses. To understand the influence of age on cerebral responses, we used contact heat‐evoked potentials (CHEPs) to investigate the physiology of cerebral responses to thermal stimuli in 70 healthy subjects (33 men and 37 women, 39.56 ± 12.12 years of age). With heat stimulation of fixed intensity (51°C) on the distal forearm and distal leg, CHEPs revealed consistent waveforms with an initial negative peak (N1 latency: 398.63 ± 28.55 and 449.03 ± 32.21 ms for upper and lower limbs) and a later positive peak (P1 latency: 541.63 ± 37.92 and 595.41 ± 39.24 ms for upper and lower limbs) with N1–P1 interpeak amplitude of 42.30 ± 12.57 μV in the upper limb and 39.67 ± 12.03 μV in the lower limb. On analyses with models of multiple linear regression, N1–P1 amplitudes were negatively correlated with age and N1 latencies were correlated with gender, with females having shorter latencies. The verbal rating scale (VRS) for pain perception was higher in females than males, and decreased with aging. In addition, VRS paralleled changes in N1–P1 amplitude and N1 latency; the higher the VRS, the shorter the N1 latency and the higher the N1–P1 amplitude. These results provide evidence that CHEPs are influenced significantly by aging, corresponding to aging‐related changes in thermal pain perception. Muscle Nerve, 2007

Distinct and shared cerebral activations in processing innocuous versus noxious contact heat revealed by functional magnetic resonance imaging

Whether innocuous heat (IH)‐exclusive brain regions exist and whether patterns of cerebral responses to IH and noxious heat (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 IH (38°C) and NH (44°C) applied to the foot. Group activation maps demonstrated three 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, 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. These results suggest that distinct and shared spatial and temporal patterns of cerebral networks are responsible for the perception of IH and NH. Hum Brain Mapp, 2010.

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.

fMRI evidence of degeneration-induced neuropathic pain in diabetes: Enhanced limbic and striatal activations

Persistent neuropathic pain due to peripheral nerve degeneration in diabetes is a stressful symptom; however, the underlying neural substrates remain elusive. This study attempted to explore neuroanatomical substrates of thermal hyperalgesia and burning pain in a diabetic cohort due to pathologically proven cutaneous nerve degeneration (the painful group). By applying noxious 44°C heat stimuli to the right foot to provoke neuropathic pain symptoms, brain activation patterns were compared with those of healthy control subjects and patients with a similar degree of cutaneous nerve degeneration but without pain (the painless group). Psychophysical results showed enhanced affective pain ratings in the painful group. After eliminating the influence of different pain intensity ratings on cerebral responses, the painful group displayed augmented responses in the limbic and striatal structures, including the perigenual anterior cingulate cortex (ACC), superior frontal gyrus, medial thalamus, anterior insular cortex, lentiform nucleus (LN), and premotor area. Among these regions, blood oxygen level‐dependent (BOLD) signals in the ACC and LN were correlated with pain ratings to thermal stimulations in the painful group. Furthermore, activation maps of a simple regression analysis as well as a region of interest analysis revealed that responses in these limbic and striatal circuits paralleled the duration of neuropathic pain. However, in the painless group, BOLD signals in the primary somatosensory cortex and ACC were reduced. These results suggest that enhanced limbic and striatal activations underlie maladaptive responses after cutaneous nerve degeneration, which contributed to the development and maintenance of burning pain and thermal hyperalgesia in diabetes. Hum Brain Mapp 34:2733–2746, 2013.

Skin Denervation and Its Clinical Significance in Late-Stage Chronic Kidney Disease

OBJECTIVE To investigate the skin innervation and its clinical significance in late-stage chronic kidney disease (CKD). DESIGN Case series. SETTING National Taiwan University Hospital, Taipei, Taiwan. PATIENTS Forty consecutive nondiabetic patients with late-stage CKD (14 female and 26 male; mean [SD] age, 60.7 [12.3] years), including 2 cases with stage 3 CKD, 6 with stage 4 CKD, and 32 with stage 5 CKD, ie, end-stage kidney disease. INTERVENTIONS Clinical evaluation of neurological deficits, nerve conduction study, autonomic function tests, and a 3-mm-diameter skin biopsy specimen taken from the distal leg. MAIN OUTCOME MEASURES Quantitation of epidermal innervation, parameters of nerve conduction study, R-R interval variability, and sympathetic skin response. RESULTS Clinically, 21 patients (52.5%) were symptomatic with paresthesia over the limbs or autonomic symptoms. The intraepidermal nerve fiber (IENF) density was markedly reduced in patients with CKD compared with age- and sex-matched controls (mean [SD], 2.8 [2.0] vs 8.6 [2.8] fibers/mm; P < .001). Skin denervation was observed in 27 patients (67.5%). Fifteen patients (37.5%) had abnormalities on nerve conduction studies, and 29 patients (72.5%) had abnormal results on autonomic function tests. By analysis with multiple regression models, the IENF density was negatively correlated with the duration of renal disease (P = .02). Additionally, the R-R interval variability at rest was linearly correlated with the IENF density (P = .02) and the absence of sympathetic skin responses at the soles was associated with reduced IENF density (P = .03). CONCLUSIONS Small-fiber sensory and autonomic neuropathies constitute the major form of neuropathy in late-stage CKD. Furthermore, skin denervation was associated with the duration of renal disease.

Effect of aging on the cerebral processing of thermal pain in the human brain.

Summary Neural activity in the middle insula and primary somatosensory cortex mediates the influence of age on heat pain perception across the adult lifespan. Abstract The perception of pain changes as people age. However, how aging affects the quality of pain and whether specific pain‐processing brain regions mediate this effect is unclear. We hypothesized that specific structures in the cerebral nociceptive system mediate the effect of aging on the variation in different pain psychophysical measures. We examined the relationships between painful heat stimulation to the foot and both functional magnetic resonance imaging signals and gray matter volume in 23 healthy subjects (aged 25˜71 years). Increased age was related to decreased subjective ratings of overall pain intensity and the “sharp” quality of pain. Group activation maps of multiple linear regression analyses revealed that age predicted responses in the middle insular cortex (IC) and primary somatosensory cortex (S1) to pain stimuli after controlling for their gray matter volumes. Blood oxygenation level‐dependent signals in the contralateral middle IC and S1 were related to ratings of “sharpness,” but not any affective descriptors of pain. Importantly, activity in the contralateral middle IC specifically mediated the effect of age on overall pain perception, whereas activity in the contralateral S1 mediated the relationship between age and sharp sensation to pain. The analyses of gray matter volume revealed that key nociceptive cerebral regions did not undergo significant age‐related gray matter loss. However, the volume of the cingulate cortex covaried with pain perception after adjusting for corresponding neural activity to pain. These results suggest that age‐related functional alterations in pain‐processing regions are responsible for changes in pain perception during normal aging.

Peripheral nerve disease in SARS: Report of a case

Severe acute respiratory syndrome (SARS), an infection caused by a novel coronavirus,1 is a life-threatening respiratory disease, which has broken out worldwide. Although the clinical features in the epidemic areas have been reported in detail,2 no neurologic manifestations have been mentioned. We report a SARS patient who developed acute paresthesia and weakness in her lower limbs during the period of mechanical ventilator support. The husband of a previously well 51-year-old woman returned to Taiwan in February 2003 from a 16-day stay in Guangdong, China, and began to experience fever (>38 °C), cough, and myalgia on February 25. Progressive respiratory distress was noted, and chest x-ray (CXR) showed bilateral pneumonia. He was intubated on March 10. Based on the traveling history, clinical manifestations, and CXR findings, he was diagnosed with probable SARS.3 His wife then developed high fever (39.1 °C), sore throat, watery diarrhea, and cough with dyspnea. Her CXR taken on March 14 showed increased infiltration in the right lower lobe. Laboratory studies showed raised glutamic-pyruvic transaminase and lactate dehydrogenase …

Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connectivity of the limbic system after peripheral nerve degeneration.

Abstract Small-fiber neuropathy (SFN) is hallmarked by degeneration of small unmyelinated peripheral nerve fibers in the skin. Traditionally, it has been considered as a pure disorder of the peripheral nervous system. Nevertheless, previous work found that dysfunction of skin nerves led to abnormal recruitment of pain-related regions, suggesting that the brain may be affected in SFN. This report combined structural and functional magnetic resonance imaging to identify structural and functional changes in the brain of 19 patients with SFN compared with 17 healthy controls. We applied tensor-based morphometry to detect brain structural alterations in SFN. Greater volume reduction in pain-processing regions, particularly the bilateral anterior cingulate cortices (ACCs), was associated with greater depletion of intraepidermal nerve fibers, a pathological biomarker of skin nerve degeneration. Based on the hypothesis that structural alterations in the pain-processing regions might impair their functional connectivity, we further applied psychophysiological interaction analysis to assess functional connectivity of the ACCs during noxious heat stimulation. There was significant reduction in functional connectivity from the ACCs to the limbic areas (the parahippocampal gyrus and the posterior cingulate cortex), pain-processing area (the insula), and visuospatial areas (the cuneus). Moreover, the degree of reduction in functional connectivity for the ACC to the amygdala and the precuneus was linearly correlated with the severity of intraepidermal nerve fiber depletion. Our findings suggest that SFN is not a pure peripheral nervous system disorder. The pain-related brain networks tend to break into functionally independent components, with severity linked to the degree of skin nerve degeneration.

Progress in the treatment of small fiber peripheral neuropathy

Small fiber neuropathy is a syndrome of diverse disease etiology because of multiple pathophysiologic mechanisms with major presentations of neuropathic pain and autonomic symptoms. Over the past decade, there has been substantial progress in the treatments for neuropathic pain, dysautonomia and disease-modifying strategy. In particular, anticonvulsants and antidepressants alleviate neuropathic pain based on randomized clinical trials.