Chi- Chao

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

Abstract  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 48.61 ± 14.10 (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

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

Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser

Objective: Familial amyloid polyneuropathy (FAP) due to amyloidogenic transthyretin (TTR) is often associated with impairment of thermonociceptive functions. This study investigated skin innervation and its clinical significance in genetically defined FAP due to a hot-spot Ala97Ser TTR mutation (Ala97Ser). Methods: Skin biopsies were performed on the distal leg of patients with Ala97Ser, and intraepidermal nerve fiber (IENF) densities were quantified. Results: There were 19 unrelated patients with Ala97Ser manifesting a late-onset (59.47 ± 5.70 years) generalized neuropathy with disabling motor, sensory, and autonomic symptoms. Against a background of a slowly progressive course, 7 patients (36.8%) exhibited additional rapid declines in neurologic deficits, which were associated with elevation of the protein content in the CSF (p < 0.001). The IENF density was markedly reduced in Ala97Ser patients compared to age- and gender-matched controls (0.99 ± 1.11 vs 8.31 ± 2.87 fibers/mm, p < 0.001). Skin denervation was present in all patients and was lower in patients with a higher disability grade (0.17 ± 0.26 vs 1.37 ± 1.16 fibers/mm, p = 0.003). Albuminocytologic dissociation in the CSF was observed in 14 patients (73.7%), and the IENF density was negatively correlated with the CSF protein concentration (p = 0.015). Conclusions: Skin denervation was common in Ala97Ser, and degeneration of cutaneous nerve terminals was correlated with the severity of clinical phenotypes and the level of CSF protein.

Procedural Safety and Potential Vascular Complication of Endovascular Recanalization for Chronic Cervical Internal Carotid Artery Occlusion

Background—Patients with chronic cervical internal carotid artery occlusion (ICAO) and cerebral ischemia may benefit from revascularization. The feasibility of endovascular recanalization for chronic ICAO has been reported recently, but its safety is still unproven. We report the follow-up results of 54 chronic ICAO patients who underwent endovascular recanalization, focusing on potential vascular complications and corresponding management. Methods and Results—Endovascular recanalization for chronic ICAO was attempted in 54 consecutive patients (48 men; 69.2±9.8 years old) with either recurrent neurological deficit or objective ipsilateral hemisphere ischemia. Mean duration from occlusion documentation to the procedure was 237±327 days (range, 56 to 1424 days). Adverse events while in the hospital and during the 3-month follow-up were recorded. Successful recanalization was achieved in 35 of 54 patients (65%). Three-month cumulative stroke and death rate was 4% (2 of 54), including 1 in-hospital fatal nonipsilateral stroke and 1 in-hospital minor ipsilateral stroke secondary to systemic hypotension. Vascular complications developed in 3 of 54 patients (6%), including 1 late pseudoaneurysm formation 3 months after recanalization, 1 immediate carotid-cavernous fistula after recanalization, and 1 minor extravasation at carotid bifurcation after failed recanalization. However, no clinical sequela was noted with close follow-up and adequate management. Conclusion—Certain immediate or delayed vascular complications may develop during or after the endovascular recanalization for chronic ICAO. Although periprocedural death and stroke rate is limited in our study, further study combining neuroimaging tools and cognitive function evaluation is mandatory to assess its utility and appropriateness in patients with chronic ICAO.

Neurocognitive Improvement After Carotid Artery Stenting in Patients With Chronic Internal Carotid Artery Occlusion and Cerebral Ischemia

Background and Purpose— Chronic cerebral hypoperfusion may lead to impairment in neurocognitive performance in patients with chronic internal carotid artery occlusion, and the effects of carotid artery stenting on neurocognitive function have been unclear. Methods— We prospectively enrolled 20 chronic internal carotid artery occlusion patients with objective ipsilateral hemisphere ischemia, in whom carotid artery stenting was attempted. Functional assessments, including the National Institutes of Health Stroke Scale, Barthel Index, and a battery of neuropsychological tests, including the Mini-Mental State Examination, Alzheimer Disease Assessment Scale–Cognitive Subtest, verbal fluency, and Color Trail Making A and B, were administered before and 3 months after intervention. Results— Successful recanalization was achieved in 12 of 20 patients (60%). There was no procedural or new cerebral ischemic event, except for 1 intracranial hemorrhage, which occurred during the procedure and had neurologic sequelae; this case was excluded from analysis. The demographics and baseline cognitive performance were similar between the group with a successful outcome (group 1, n=12) and patients who did not (group 2, n=7). Ten of 12 patients in group 1 had improvement in ipsilateral brain perfusion after the procedure, but none in group 2 had improvement. Significant improvement in the scores on the Alzheimer Disease Assessment Scale–Cognitive Subtest (before, 7.7±8.9 versus after, 5.7±7.1; P=0.024), Mini-Mental State Examination (before, 25.8±3.8 versus after, 27.7±2.7; P=0.015), and Color Trail Making A (before, 123.2±68.6 versus after, 99.3±51.5; P=0.017) were found in group 1 but not in group 2. Conclusions— Successful carotid artery stenting improves global cognitive function as well as attention and psychomotor processing speed in patients with chronic internal carotid artery occlusion.

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.

Carotid stenting improves cognitive function in asymptomatic cerebral ischemia

OBJECTIVES Asymptomatic critical internal carotid artery (ICA) stenosis may lead to cognitive impairment. Carotid stenting (CS) may improve cerebral perfusion, but its impact on neuro-cognitive function has been controversial. METHODS We prospectively enrolled 34 asymptomatic patients with unilateral ICA stenosis or occlusion, in whom CS was attempted. Computed tomography cerebral perfusion (CTP), and functional assessments including National Institutes of Health Stoke Scale (NIHSS), Bathel Index (BI), and a battery of neuropsychological tests including Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-Cognitive Subtest (ADAS-Cog), verbal fluency, and Color Trail Making A and B, were done prior to and 3 months after the procedure. RESULTS Successful CS was achieved in 28 of 34 patients (82%). Based on the baseline CTP finding and intervention result, patients were divided into three groups: group I (n=6) as ipsilateral cerebral ischemia with failed CS procedure, group II (n=17) as ipsilateral cerebral ischemia with successful CS procedure, and group III (n=11) as normal baseline CTP with successful CS procedure. The demographics and baseline cognitive performances were similar among the three groups. In group II, there were significant improvement in Alzheimer Disease Assessment Scale (pre 6.8 ± 4.3 vs post 4.9 ± 2.8, p=0.033), Mini-Mental State Examination Score (pre 25.8 ± 3.8 vs post 27.4 ± 3.5, p=0.007), and Color Trail test A (pre 120.4 ± 73.9s vs post 95.8 ± 57.6s, p=0.004) after CS. In groups I and III, however, no significant difference was observed in any of the cognitive tests. CONCLUSIONS Successful CS improves neurocognitive function in asymptomatic ICA stenosis or occlusion with objective ipsilateral ischemia.