Improved acquisition of contact heat evoked potentials with increased heating ramp.

Contact heat evoked potentials (CHEPs) represent an objective and non-invasive measure to investigate the integrity of the nociceptive neuraxis. The clinical value of CHEPs is mostly reflected in improved diagnosis of peripheral neuropathies and spinal lesions. One of the limitations of conventional contact heat stimulation is the relatively slow heating ramp (70 °C/s). This is thought to create a problem of desynchronized evoked responses in the brain, particularly after stimulation in the feet. Recent technological advancements allow for an increased heating ramp of contact heat stimulation, however, to what extent these improve the acquisition of evoked potentials is still unknown. In the current study, 30 healthy subjects were stimulated with contact heat at the hand and foot with four different heating ramps (i.e., 150 °C/s, 200 °C/s, 250 °C/s, and 300 °C/s) to a peak temperature of 60 °C. We examined changes in amplitude, latency, and signal-to-noise ratio (SNR) of the vertex (N2-P2) waveforms. Faster heating ramps decreased CHEP latency for hand and foot stimulation (hand: F = 18.41, p < 0.001; foot: F = 4.19, p = 0.009). Following stimulation of the foot only, faster heating ramps increased SNR (F = 3.32, p = 0.024) and N2 amplitude (F = 4.38, p = 0.007). Our findings suggest that clinical applications of CHEPs should consider adopting faster heating ramps up to 250 °C/s. The improved acquisition of CHEPs might consequently reduce false negative results in clinical cohorts. From a physiological perspective, our results demonstrate the importance of peripherally synchronizing afferents recruitment to satisfactorily acquire CHEPs.

Metabolite activity in the anterior cingulate cortex during a painful stimulus using functional MRS.

To understand neurochemical brain responses to pain, proton magnetic resonance spectroscopy (1H-MRS) is used in humans in vivo to examine various metabolites. Recent MRS investigations have adopted a functional approach, where acquisitions of MRS are performed over time to track task-related changes. Previous studies suggest glutamate is of primary interest, as it may play a role during cortical processing of noxious stimuli. The objective of this study was to examine the metabolic effect (i.e., glutamate) in the anterior cingulate cortex during noxious stimulation using fMRS. The analysis addressed changes in glutamate and glutamate + glutamine (Glx) associated with the onset of pain, and the degree by which fluctuations in metabolites corresponded with continuous pain outcomes. Results suggest healthy participants undergoing tonic noxious stimulation demonstrated increased concentrations of glutamate and Glx at the onset of pain. Subsequent reports of pain were not accompanied by corresponding changes in glutamate of Glx concentrations. An exploratory analysis on sex revealed large effect size changes in glutamate at pain onset in female participants, compared with medium-sized effects in male participants. We propose a role for glutamate in the ACC related to the detection of a noxious stimulus.

Normative data of contact heat evoked potentials from the lower extremities.

Contact heat evoked potentials (CHEPs) have become an acknowledged research tool in the assessment of the integrity of the nociceptive system and gained importance in the diagnostic work-up of patients with suspected small fiber neuropathy. For the latter, normative values for CHEP amplitude and latency are indispensable for a clinically meaningful interpretation of the results gathered in patients. To this end, CHEPs were recorded in 100 healthy subjects over a wide age range (20-80 years) and from three different dermatomes of the lower extremities (L2, L5, and S2). A normal baseline (35-52 °C) and increased baseline stimulation (42-52 °C) were applied. Statistical analysis revealed significant effects of stimulation site, stimulation intensity, and sex on CHEP parameters (N2 latency, N2P2 amplitude, and NRS). Significant positive correlations of body height with N2 latency, and pain ratings with N2P2 amplitudes were observed. This is the first time that normative values have been obtained from multiple dermatomes of the lower extremities. The present dataset will facilitate the clinical application of CHEPs in the neurophysiological diagnosis of small fiber neuropathy and by discerning pathological findings help establish a proximal-distal gradient of nerve degeneration in polyneuropathies.

Contact heat evoked potentials: Reliable acquisition from lower extremities.

OBJECTIVE: To investigate test-retest reliability of contact heat evoked potentials (CHEPs) from lower extremities using two different stimulation protocols, i.e., normal and increased baseline temperature. METHODS: A total of 32 able-bodied subjects were included and a subset (N = 22) was retested. CHEPs were recorded from three different dermatomes of the lower extremity (i.e., L2, L5, and S2). Test-retest reliability of CHEPs acquisition after simulation in various lower limb dermatomes using different stimulation protocols was analyzed. RESULTS: The study revealed an improved acquisition of CHEPS employing the increased baseline protocol, particularly when stimulating more distal sites, i.e., dermatome L5 and S2. Based on repeatability coefficients, CHEP latency (N2 potential) emerged as the most robust CHEP parameter. Although CHEP amplitudes (N2P2 complex) and pain ratings were decreased in the retest, amplitudes still showed fair to excellent intraclass correlation coefficients using normal baseline or increased baseline temperature, respectively. CONCLUSIONS: This is the first study to demonstrate that CHEPs acquisition from the lower extremities is improved by increasing the baseline temperature of the thermode. SIGNIFICANCE: This study highlights the usability of CHEPs as a viable diagnostic method to study small fiber integrity.

Discrepancy between perceived pain and cortical processing: A voxel-based morphometry and contact heat evoked potential study.

OBJECTIVES: The purpose of this study was to determine if local gray and white matter volume variations between subjects could account for variability in responses to CHEP stimulation. METHODS: Structural magnetic resonance imaging was used to perform voxel-based morphometry (VBM) of gray and white matter in 30 neurologically healthy subjects. Contact heat stimulation was performed on the dorsum of the right hand at the base of the thumb. Evoked potentials were acquired from a vertex-recording electrode referenced to linked ears. RESULTS: Controlling for age, total intracranial volume, and skull/scalp thickness, CHEP amplitude and pain rating were not significantly correlated between subjects. A VBM region of interest approach demonstrated a significant interaction between pain rating and N2 amplitude in the right insular cortex (p<0.05, family-wise error corrected, FWE). In white matter, a significant interaction was localized in the right inferior frontal occipital fasciculus (IFOF, p<0.05 FWE). CONCLUSIONS: Accounting for gray matter volume in the right insular cortex, resulted in a significant relationship between CHEP amplitude and pain rating. SIGNIFICANCE: This finding suggests that the discrepancy between pain ratings and the amplitude of evoked potentials is not solely related to measurement artifact, but rather attributable, in part, to anatomical differences between subjects.

Relationship between chronic pain and brain reorganization after deafferentation: A systematic review of functional MRI findings.

BACKGROUND: Mechanisms underlying the development of phantom limb pain and neuropathic pain after limb amputation and spinal cord injury, respectively, are poorly understood. The goal of this systematic review was to assess the robustness of evidence in support of "maladaptive plasticity" emerging from applications of advanced functional magnetic resonance imaging (MRI). METHODS: Using MeSH heading search terms in PubMed and SCOPUS, a systematic review was performed querying published manuscripts. RESULTS: From 146 candidate publications, 10 were identified as meeting the inclusion criteria. Results from fMRI investigations provided some level of support for maladaptive cortical plasticity, including longitudinal studies that demonstrated a change in functional organization related to decreases in pain. However, a number of studies have reported no relationship between reorganization, pain and deafferentation, and emerging evidence has also suggested the opposite - that is, chronic pain is associated with preserved cortical function. CONCLUSION: Based solely on advanced functional neuroimaging results, there is only limited evidence for a relationship between chronic pain intensity and reorganization after deafferentation. The review demonstrates the need for additional neuroimaging studies to clarify the relationship between chronic pain and reorganization.

Heterotopic and homotopic nociceptive conditioning stimulation: distinct effects of pain modulation.

BACKGROUND: Within an area, habituation and sensitization represent well-established modulatory effects to repetitive noxious input. Less is known regarding the nociceptive conditioning effects between body sites - i.e., how stimulating one site may affect another. Therefore, we investigated the effects of nociceptive stimulation of anatomically distinct locations (shoulder and hand) on pain rating and evoked potentials (i.e., contact heat-evoked potentials). METHODS: The effect of stimulation order was assessed in eight healthy subjects. The shoulder was examined before the hand or the hand before the shoulder. All subjects underwent both conditions (shoulder before hand and hand before shoulder) on separate days. In an additional 30 subjects (total n = 38), between retesting the shoulder or the hand, conditioning stimulation in the respective other location (i.e., hand or shoulder) was applied. Both analyses focused upon changes in the magnitude of evoked pain responses in relation to the respective area being conditioned by heterotopic stimulation. RESULTS: When the shoulder was stimulated before the hand, N2P2 amplitude was significantly reduced. In contrast, stimulating the hand before the shoulder resulted in significant response increments (shorter N2 latency). Additionally, conditioning stimulation of the hand resulted in increased pain rating to shoulder stimulation. CONCLUSIONS: Overall, these findings indicate that response modulation to noxious contact heat stimulation depends upon conditioning stimulus location. These effects represent changes beyond conventional habituation due to repeated stimulation in the same area.

Increased baseline temperature improves the acquisition of contact heat evoked potentials after spinal cord injury.

OBJECTIVE: To investigate the effect of increasing the skin surface baseline temperature for contact heat evoked potentials (CHEPs). METHODS: CHEPs were studied in healthy subjects and subjects with chronic cervical spinal cord injury (SCI) using a conventional 35°C (condition 1) or increased 42-45°C baseline temperature (condition 2). A third condition was used to standardize the contact heat stimulus duration from the different baseline temperatures. Changes in peak latency and N2P2 amplitude of the CHEPs and rating of perceived intensity were examined between conditions. RESULTS: In healthy subjects, increasing the baseline temperature for contact heat stimulation significantly increased the rating of perceived intensity (conditions 2 and 3), as well as the amplitude of CHEPs (condition 2 only). Following SCI, an increased baseline temperature facilitated perception of contact heat stimulation and evoked potentials could be recorded from dermatomes that were insensitive to contact heat from a conventional baseline temperature. CONCLUSIONS: Enhancing the acquisition of CHEPs can be achieved by increasing the baseline temperature. This effect can be attributed, in part, to shortening the stimulation duration. SIGNIFICANCE: After SCI, increasing the baseline temperature for CHEPs in dermatomes with absent or diminished sensation improved the neurophysiological resolution of afferent sparing.

Feasibility and efficacy of upper limb robotic rehabilitation in a subacute cervical spinal cord injury population.

STUDY DESIGN: Multi-center pilot study. OBJECTIVES: To investigate the use of an upper limb robotic rehabilitation device (Armeo Spring, Hocoma AG, Switzerland) in a subacute cervical spinal cord injury (SCI) population. SETTING: Two Canadian inpatient rehabilitation centers. METHODS: Twelve subjects (motor level C4-C6, ASIA Impairment Scale A-D) completed the training, which consisted of 16.1±4.6 sessions over 5.2±1.4 weeks. Two types of outcomes were recorded: (1) feasibility of incorporating the device into an inpatient rehabilitation program (compliance with training schedule, reduction in therapist time required and subject questionnaires) and (2) efficacy of the robotic rehabilitation for improving functional outcomes (Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP), action research arm test, grip dynamometry and range of motion). RESULTS: By the end of the training period, the robot-assisted training was shown to require active therapist involvement for 25±11% (mean±s.d.) of the total session time. In the group of all subjects and in a subgroup composed of motor-incomplete subjects, no statistically significant differences were found between intervention and control limbs for any of the outcome measures. In a subgroup of subjects with partial hand function at baseline, the GRASSP-Sensibility component showed a statistically significant increase (6.0±1.6 (mean±s.e.m.) point increase between baseline and discharge for the intervention limbs versus 1.9±0.9 points for the control limbs). CONCLUSION: The pilot results suggest that individuals with some preserved hand function after SCI may be better candidates for rehabilitation training using the Armeo Spring device.

Characterization of neurological recovery following traumatic sensorimotor complete thoracic spinal cord injury.

STUDY DESIGN: Retrospective, longitudinal analysis of sensory, motor and functional outcomes from individuals with thoracic (T2-T12) sensorimotor complete spinal cord injury (SCI). OBJECTIVES: To characterize neurological changes over the first year after traumatic thoracic sensorimotor complete SCI. METHODS: A dataset of 399 thoracic complete SCI subjects from the European Multi-center study about SCI (EMSCI) was examined for neurological level, sensory levels and sensory scores (pin-prick and light touch), lower extremity motor score (LEMS), ASIA Impairment Scale (AIS) grade, and Spinal Cord Independence Measure (SCIM) over the first year after SCI. RESULTS: AIS grade conversions were limited. Sensory scores exhibited minimal mean change, but high variability in both rostral and caudal directions. Pin-prick and light touch sensory levels, as well as neurological level, exhibited minor changes (improvement or deterioration), but most subjects remained within one segment of their initial injury level after 1 year. Recovery of LEMS occurred predominantly in subjects with low thoracic SCI. The sensory zone of partial preservation (ZPP) had no prognostic value for subsequent recovery of sensory levels or LEMS. However, after mid or low thoracic SCI, ≥3 segments of sensory ZPP correlated with an increased likelihood for AIS grade conversion. CONCLUSION: The data suggest that a sustained deterioration of three or more thoracic sensory levels or loss of upper extremity motor function are rare events and may be useful for tracking the safety of a therapeutic intervention in early phase acute SCI clinical trials, if a significant proportion of study subjects exhibit such an ascent.

Stress and DNA assembly differences on cantilevers gold coated by resistive and e-beam evaporation techniques.

Changes in the sign of differential surface stress of gold-coated cantilevers produced by thiol-derivatized single-stranded DNA immobilization are observed, depending on the method used to deposit the gold. While the DNA immobilization on e-beam gold-coated cantilevers produces a compressive differential surface stress in the metallic layer, the opposite is observed for resistively coated cantilevers under the same immobilization conditions. The gold films exhibit quite a similar morphology, and the immobilization differences seem to be related to the charge state of the metallic layer surface. This in turn produces a different distribution of the orientation of the DNA strands on the gold layer. A tentative explanation for the observed effect is proposed.

Carbon monoxide-releasing molecule tricarbonyldichlororuthenium (II) dimer induces concentration-dependent alterations in the electrophysiological properties of axons in mammalian spinal cord.

Traumatic spinal cord injury (SCI) typically involves intraparenchymal hemorrhage and a cascade of inflammatory and cytotoxic processes leading to tissue necrosis and apoptosis. A consequence of the hemorrhage is the accumulation of deoxygenated heme proximal and distal to the epicenter of the lesion. The heme oxygenase (HO) system is an endogenous heme degradation system and is upregulated following neurotrauma. The breakdown of heme via HO activity yields the byproducts carbon monoxide (CO), biliverdin, and iron. CO has documented neuromodulatory properties; however, the effects of elevated concentrations of CO on axonal conduction in the spinal cord have not previously been studied. The present study tested the hypothesis that CO causes alterations in the electrophysiological properties of axons within the isolated guinea-pig spinal cord. Ex vivo spinal cord preparations were exposed to 100, 500, and 1000 microM concentrations of the carbon monoxide-releasing molecule (CORM) 2 for 30 min in a double sucrose gap electrophysiological recording system and the compound action potential (CAP) and membrane potential (CMP) were recorded continuously during pretreatment, CORM-2 treatment, and washout (30 min) with Krebs' solution. CAP amplitude and area were significantly (P<0.05) reduced following treatment with 500 and 1000 microM CORM-2 and did not recover during washout. No effect on CMP was observed, however, stimulus-peak latency did increase significantly (P<0.05) following CORM-2 treatment at these concentrations, and a decrease in the amplitude of the second CAP elicited by paired-pulse stimulation was also evident at interpulse intervals of 2 and 4 ms. These results are consistent with a CO-induced alteration in axonal conduction, possibly attributable to modified Na+ channel conductance. They also identify a new mechanism by which post-traumatic hemorrhage contributes to the neurological deficits observed following SCI.

Research priorities for urological care following spinal cord injury: recommendations of an expert panel.

OBJECTIVE: A multidisciplinary panel of experts from Canada and the United States was convened by the Ontario Neurotrauma Foundation (ONF) to establish research priorities in the area of urological care following spinal cord injury (SCI). DESIGN: The panel reviewed a synthesis of published literature in five areas of urology, identified emerging opportunities in the private and public sector, and used a modified Delphi approach to reach consensus on priorities for funding. RESULTS: The panel recommendations included: clinical trials of the safety and efficacy of M3 receptor specific anti-muscarinic agents for bladder hyperactivity in SCI patients; development and testing of protocols for sacral nerve electrostimulation without sacral afferent neurectomy for management of micturition - including selective stimulation of sacral nerve fibers, high frequency blocking of the pudendal nerve to minimize the risk of urethral sphincter co-contraction and genital nerve stimulation for bladder inhibition and incontinence management; clinical trials of the efficacy and safety of intra-urethral valve catheters; trials of the efficacy of probiotics for bacterial interference i.e. to reduce colonization by uropathogens and manage the dual problems of infection and pathogen resistance to anti-microbials: innovations in the prevention or treatment of stone disease (ureteral, bladder and kidney). CONCLUSIONS: The recommendations form the strategic priorities of the ONF SCI grants program for Ontario-based investigators and their partnerships with out-of-province collaborators and organizations.

Interface double-exchange ferromagnetism in the Mn-Zn-O system: new class of biphase magnetism.

In this Letter, we experimentally show that the room temperature ferromagnetism in the Mn-Zn-O system recently observed is associated with the coexistence of Mn(3+) and Mn(4+) via a double-exchange mechanism. The presence of the ZnO around MnO(2) modifies the kinetics of MnO(2)-->Mn(2)O(3) reduction and favors the coexistence of both Mn oxidation states. The ferromagnetic phase is associated with the interface formed at the Zn diffusion front into Mn oxide, corroborated by preparing thin film multilayers that exhibit saturation magnetization 2 orders of magnitude higher than bulk samples.

Nanostructure and magnetic properties of the MnZnO system, a room temperature magnetic semiconductor?

The magnetic properties of the system MnZnO prepared by conventional ceramic procedures using ZnO and MnO(2) starting powders are studied and related to the nanostructure. Thermal treatment at 500 °C produces a ferromagnetic phase, although this temperature is not high enough to promote proper sintering; thus the thermally treated compact shows brittle characteristics of unreacted and poorly densified ceramic samples. Scanning electron microscopy and x-ray analysis reveal the appearance of a new phase, most probably related to the diffusion of Zn into MnO(2) oxide nanocrystals. The magnetic properties deviate considerably from what would be expected of an unreacted mixture of ZnO (diamagnetic) and MnO(2) particles (paramagnetic above 100 K and anti-ferromagnetic below that temperature), exhibiting a ferromagnetic like behaviour from 5 to 300 K and beyond mixed with a paramagnetic component. The ferromagnetic phase seems to be originated by diffusion at the nanoscale of Zn into MnO(2) grains. The Curie temperature of the ferromagnetic phase, once the paramagnetic component has been subtracted from the hysteresis loops, is measured to be 450 K. EPR resonance experiments from 100 to 600 K confirm a ferromagnetic to paramagnetic like transition above room temperature for these materials.

Ionic shell and subshell structures in aluminum and gold nanocontacts.

Conductance histograms of aluminum and gold nanocontact rupture are studied experimentally and simulated using embedded atom potentials to assess the interplay between electronic and structural properties at room temperature. Our results reveal a crossover from quantized conductance structures to crystalline faceting or geometric shell/subshell structures at 300 K. The absence of electronic shell structure in gold and aluminum is in stark contrast with the behavior of alkaline metal nanowires which emulate their cluster counterparts. Semiclassical arguments suggest why rapid dominance of ionic structures takes place, and possible nanowire architectures are proposed in consistency with both the experimental and simulated nanocontact data.

Intestinal mucosa is a target tissue for pancreatic polypeptide.

Studies were carried out to identify mammalian tissues capable of specifically binding mammalian pancreatic polypeptide (PP). Bovine PP (bPP) radiolabeled with 125I was purified by HPLC to yield [125I]iodo-(Tyr-27) bPP. The label was injected into three pairs of fasted littermate dogs and allowed to circulate for 5 min. One of the dogs was a control which received an excess of unlabeled porcine PP to provide competition for receptor binding. Unbound bPP was removed by perfusion with Krebs-Ringer bicarbonate and the tissue fixed in situ with Karnovsky's fixative. Tissue samples from various organs were removed, weighed, and counted. The entire gastrointestinal tract demonstrated high levels of 125I after injection of the labeled peptide. The duodenum, jejunum, ileum, and colon were the only tissues to exhibit specific binding of bPP. These tissues (mucosal and muscle layers) from experimental animals exhibited 31-76% higher binding than the corresponding tissues from the control animals. Sections of the gastrointestinal tract were scraped to separate the mucosal layer from the underlying muscle layer. The mucosal layer of the duodenum, jejunum, and ileum exhibited 145-162% increases in binding compared to the control animals. The muscle layer of these tissues demonstrated no significant increase. These findings demonstrate that mucosal layer of the small intestine is a target tissue for mammalian PP.

Identification of pancreatic polypeptide secretagogues in canine duodenal mucosa.

The second phase of pancreatic polypeptide (PP) release after a meal is thought to occur via a vagal-cholinergic-dependent pathway acting in concert with a putative humoral factor of gut origin. To identify this enteric factor(s), extracts of canine duodenal mucosa were evaluated for PP secretagogues using canine pseudoislets in a column-perifusion bioassay system. Two thermostable agents with PP secretagogue activity have been found. The smaller and predominant peptide had an apparent molecular weight slightly larger than insulin and migrated on Sephadex G-50 columns at a distribution coefficient of 0.47 +/- 0.01. This secretagogue consistently elicited 1.3-1.5 times greater PP secretory response when compared to the larger peptide, which migrated at an average distribution coefficient of 0.29 +/- 0.02. Chromatographically similar activities were found in extracts of duodenal venous plasma collected 2 h after a meal. These PP secretagogues are presumed to be unique to the duodenal mucosa since they were not observed in extracts of liver or heart. These results show that the duodenal mucosa contains PP secretagogues larger than those previously demonstrated and further support the notion that a substance of gut origin participates in the mechanism of postprandial PP release.