Proximal Stimulation Research Articles

The process of distal attribution illuminated through studies of sensory substitution.

When we interact with objects in our environment, as a general rule we are not aware of the proximal stimulation they provide, but we directly experience the external object. This process of assigning an external cause is known as distal attribution. It is extremely difficult to measure how distal attribution emerges because it arises so early in life and appears to be automatic. Sensory substitution systems give us the possibility to measure the process as it occurs online. With these devices, objects in our environment produce novel proximal stimulation patterns and individuals have to establish the link between the proximal stimulation and the distal object. This review disentangles the contributing factors that allow the nervous system to assign a distal cause, thereby creating the experience of an external world. In particular, it highlights the role of the assumption of a stable world, the role of movement, and finally that of calibration. From the existing sensory substitution literature it appears that distal attribution breaks down when one of these principles is violated and as such the review provides an important piece to the puzzle of distal attribution.

Proximally evoked soleus H-reflex to S1 nerve root stimulation in sensory neuronopathies (ganglionopathies)

Sensory neuronopathy (SNN) mimics distal sensory axonopathy. The conventional H-reflex elicited by tibial nerve stimulation (tibial H-reflex) is usually abnormal in both conditions. We evaluated the proximally evoked soleus H-reflex in response to S1 nerve root stimulation (S1 foramen H-reflex) in SNN. Eleven patients with SNN and 6 with distal sensory axonopathy were studied. Tibial and S1 foramen H-reflexes were performed bilaterally in each patient. Tibial and S1 foramen H-reflexes were absent bilaterally in all patients with SNN. In the patients with distal sensory axonopathy, tibial H-reflexes were absent in 4 and demonstrated prolonged latencies in 2, but S1 foramen H-reflexes were normal. Characteristic absence of the H-reflex after both proximal and distal stimulation reflects primary loss of dorsal root ganglion (DRG) neurons and the distinct non-length-dependent impairment of sensory nerve fibers in SNN.

Lack of functionally active sweet taste receptors in the jejunum in vivo in the rat

BackgroundWhen studied in enterocyte-like cell lines (Caco-2 and RIE cells), agonists and antagonists of the sweet taste receptor (STR) augment and decrease glucose uptake, respectively. We hypothesize that exposure to STR agonists and antagonists in vivo will augment glucose absorption in the rat. Materials and methodsAbout 30-cm segments of jejunum in anesthetized rats were perfused with iso-osmolar solutions containing 10, 35, and 100 mM glucose solutions (n = 6 rats, each group) with and without the STR agonist 2 mM acesulfame potassium and the STR inhibitor 10 μM U-73122 (inhibitor of the phospholipase C pathway). Carrier-mediated absorption of glucose was calculated by using stereospecific and nonstereospecific 14C-d-glucose and 3H-l-glucose, respectively. ResultsAddition of the STR agonist acesulfame potassium to the 10, 35, and 100 mM glucose solutions had no substantive effects on glucose absorption from 2.1 ± 0.2 to 2.0 ± 0.3, 5.8 ± 0.2 to 4.8 ± 0.2, and 15.5 ± 2.3 to 15.7 ± 2.7 μmoL/min/30-cm intestinal segment (P > 0.05), respectively. Addition of the STR inhibitor (U-73122) also had no effect on absorption in the 10, 35, and 100 mM solutions from 2.3 ± 0.1 to 2.1 ± 0.2, 7.7 ± 0.5 to 7.2 ± 0.5, and 15.7 ± 0.9 to 15.2 ± 1.1 μmoL/min/30-cm intestinal segment, respectively. ConclusionsProvision of glucose directly into rat jejunum does not augment glucose absorption via STR-mediated mechanisms within the jejunum in the rat. Our experiments show either no major role of STRs in mediating postprandial augmentation of glucose absorption or that proximal gastrointestinal tract stimulation of STR or other luminal factors may be required for absorption of glucose to be augmented by STR.

Molecular model of a soluble guanylyl cyclase fragment determined by small-angle X-ray scattering and chemical cross-linking.

Soluble guanylyl/guanylate cyclase (sGC) converts GTP to cGMP after binding nitric oxide, leading to smooth muscle relaxation and vasodilation. Impaired sGC activity is common in cardiovascular disease, and sGC stimulatory compounds are vigorously sought. sGC is a 150 kDa heterodimeric protein with two H-NOX domains (one with heme, one without), two PAS domains, a coiled-coil domain, and two cyclase domains. Binding of NO to the sGC heme leads to proximal histidine release and stimulation of catalytic activity. To begin to understand how binding leads to activation, we examined truncated sGC proteins from Manduca sexta (tobacco hornworm) that bind NO, CO, and stimulatory compound YC-1 but lack the cyclase domains. We determined the overall shape of truncated M. sexta sGC using analytical ultracentrifugation and small-angle X-ray scattering (SAXS), revealing an elongated molecule with dimensions of 115 Å × 90 Å × 75 Å. Binding of NO, CO, or YC-1 had little effect on shape. Using chemical cross-linking and tandem mass spectrometry, we identified 20 intermolecular contacts, allowing us to fit homology models of the individual domains into the SAXS-derived molecular envelope. The resulting model displays a central parallel coiled-coil platform upon which the H-NOX and PAS domains are assembled. The β1 H-NOX and α1 PAS domains are in contact and form the core signaling complex, while the α1 H-NOX domain can be removed without a significant effect on ligand binding or overall shape. Removal of 21 residues from the C-terminus yields a protein with dramatically increased proximal histidine release rates upon NO binding.

Quantitative Phosphoproteomics Reveals SLP-76 Dependent Regulation of PAG and Src Family Kinases in T Cells

The SH2-domain-containing leukocyte protein of 76 kDa (SLP-76) plays a critical scaffolding role in T cell receptor (TCR) signaling. As an adaptor protein that contains multiple protein-binding domains, SLP-76 interacts with many signaling molecules and links proximal receptor stimulation to downstream effectors. The function of SLP-76 in TCR signaling has been widely studied using the Jurkat human leukaemic T cell line through protein disruption or site-directed mutagenesis. However, a wide-scale characterization of SLP-76-dependant phosphorylation events is still lacking. Quantitative profiling of over a hundred tyrosine phosphorylation sites revealed new modes of regulation of phosphorylation of PAG, PI3K, and WASP while reconfirming previously established regulation of Itk, PLCγ, and Erk phosphorylation by SLP-76. The absence of SLP-76 also perturbed the phosphorylation of Src family kinases (SFKs) Lck and Fyn, and subsequently a large number of SFK-regulated signaling molecules. Altogether our data suggests unique modes of regulation of positive and negative feedback pathways in T cells by SLP-76, reconfirming its central role in the pathway.

Collision Tumor of the Facial Nerve

To report a novel case of a collision tumor involving an intraparotid neurofibroma and a mastoid segment facial nerve schwannoma. Clinical capsule report. Tertiary academic referral center. A 29-year-old woman with a 2-year history of an asymptomatic enlarging left infraauricular mass and normal FN function presented to a tertiary care referral center. Computed tomography and magnetic resonance imaging demonstrated a cystic lesion in the deep portion of the parotid gland extending into the stylomastoid foramen. The patient underwent superficial parotidectomy, and a cystic parotid mass was found to be intrinsic to the intraparotid facial nerve. A portion of the mass was biopsied, and intraoperative frozen section pathology was consistent with a neurofibroma. A mastoidectomy with FN decompression was then performed until a normal-appearing segment was identified just proximal to the second genu. After biopsy, proximal facial nerve stimulation failed to elicit evoked motor potentials, and en bloc resection was performed. Final pathology demonstrated a schwannoma involving the mastoid segment and a neurofibroma involving the proximal intraparotid facial nerve. We report the first case of a facial nerve collision tumor involving an intraparotid neurofibroma and a mastoid segment facial nerve schwannoma. Benign FN sheath tumors of the parotid gland are rare but should be considered in the differential diagnosis of a parotid mass.

PWE-046 The development of human esophageal pain hypersensitivity is associated with anxiety and sympathetic nervous system activation

IntroductionExperimental acid infusion in the distal oesophagus leads to secondary hyperalgesia in the proximal oesophagus in most healthy subjects but 30% remain resistant. The factors that mediate differences in sensitisation...

Randomised clinical trial: pregabalin attenuates the development of acid‐induced oesophageal hypersensitivity in healthy volunteers – a placebo‐controlled study

Acid infusion in humans induces primary and secondary oesophageal hypersensitivity. The effects of pregabalin, a centrally-acting modulator of voltage-sensitive calcium channels, on development of acid-induced oesophageal hypersensitivity remain unknown. To study the effects of pregabalin on development of secondary oesophageal hypersensitivity in healthy humans. Placebo-controlled, double-blind, randomised, cross-over study of 15 healthy volunteers (six women, age 21-56 years). After oesophageal manometry, baseline pain thresholds (PTs) to proximal oesophageal electrical stimulation were determined using bipolar ring electrodes. A 30-min infusion of HCl was performed in the distal oesophagus followed by PT measurements at 30 and 90 min. This protocol was repeated after administration of pregabalin (dosing schedule: 75 mg twice daily for 3 days then 150 mg twice daily for 1 day and then 150 mg on the morning of study) or placebo. T0 PTs were similar in patients after receiving placebo or pregabalin [mean (s.d.) 32.9 mA (20.5) vs. 34.1 (15.7), P = 0.42]. Pregabalin reduced development of acid-induced hypersensitivity in the proximal oesophagus at 30 min [mean change in PT (C.I.) placebo -6.2 mA (-11.3 to +1.3) vs. pregabalin +0.20 mA (-2.7 to +3.3)] and 90 min [placebo -3.7 mA (-10.0 to +2.0) vs. pregabalin +0.7 mA (-4.7 to 7.3)] overall P = 0.001. Pregabalin reduced median visual analogue scale score for acid-induced pain (1/10 vs. placebo 3/10, P = 0.027). Pregabalin attenuates development of secondary hypersensitivity in the proximal oesophagus after distal oesophageal acidification; it may thus have a role in treatment of patients with proven oesophageal pain hypersensitivity.

Hepatitis B Virus Large Surface Antigen Promotes Liver Carcinogenesis by Activating the Src/PI3K/Akt Pathway

Of the three envelope glycoproteins encoded by hepatitis B virus (HBV) that are collectively referred to as HBV surface antigen (HBsAg), the large HBsAg (LHBs) glycoprotein is expressed preferentially in HBV-associated hepatocellular carcinoma. LHBs can act as an oncogene in transgenic mice, but how it contributes functionally to hepatocarcinogenesis remains unclear. In this study, we determined the molecular and functional roles of LHBs during HBV-associated hepatocarcinogenesis. LHBs increased tumor formation of hepatoma cells. Moreover, expression of LHBs but not other HBV envelope glycoproteins specifically promoted proliferation of hepatoma and hepatic cells in vitro. Mechanistic investigations revealed that these effects were caused by activation of the Src/PI3K/Akt pathway through proximal stimulation of PKCα/Raf1 signaling by LHBs. Proliferation induced by stable LHBs expression was associated with increased G(1)-S cell-cycle progression and apoptosis resistance mediated by Src kinase activation, as established in hepatocellular carcinoma clinical specimens. Importantly, LHBs-induced cellular proliferation and tumor formation were reversed by administration of the Src inhibitor saracatinib. Together, our findings suggest that LHBs promotes tumorigenesis of hepatoma cells by triggering a PKCα/Raf1 to Src/PI3K/Akt signaling pathway, revealing novel insights into the underlying mechanisms of HBV-associated hepatocarcinogenesis.

Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome

GABAergic dysfunction is implicated in hippocampal deficits of the Ts65Dn mouse model of Down syndrome (DS). Since Ts65Dn mice overexpress G-protein coupled inward-rectifying potassium (GIRK2) containing channels, we sought to evaluate whether increased GABAergic function disrupts the functioning of hippocampal circuitry. After confirming that GABAB/GIRK current density is significantly elevated in Ts65Dn CA1 pyramidal neurons, we compared monosynaptic inhibitory inputs in CA1 pyramidal neurons in response to proximal (stratum radiatum; SR) and distal (stratum lacunosum moleculare; SLM) stimulation of diploid and Ts65Dn acute hippocampal slices. Synaptic GABAB and GABAA mediated currents evoked by SR stimulation were generally unaffected in Ts65Dn CA1 neurons. However, the GABAB/GABAA ratios evoked by stimulation within the SLM of Ts65Dn hippocampus were significantly larger in magnitude, consistent with increased GABAB/GIRK currents after SLM stimulation. These results indicate that GIRK overexpression in Ts65Dn has functional consequences which affect the balance between GABAB and GABAA inhibition of CA1 pyramidal neurons, most likely in a pathway specific manner, and may contribute to cognitive deficits reported in these mice.

Effects of neurokinin-1 and 3-receptor antagonists on the defensive behavior induced by electrical stimulation of the dorsal periaqueductal gray

The dorsal periaqueductal gray (dPAG) is the main output structure for the defensive response to proximal aversive stimulation. Panic-like responses, such as freezing and escape behaviors, often result when this structure is electrically stimulated. Freezing also ensues after termination of the dPAG stimulation (post-stimulation freezing (PSF)). GABA and 5-HT have been proposed as the main neuromediators of these defense reactions. Neurokinins (NKs) also play a role in the defense reaction; however, it is unclear how the distinct types of NK receptors are involved in the expression of these fear responses. This study investigated the role of NK-1 and NK-3 receptors in the unconditioned defensive behaviors induced by electrical stimulation of the dPAG of rats, with and without previous experience with contextual fear conditioning (CFC). Spantide (100 ρmol/0.2 μl) and SB 222200 (50 and 100 ρmol/0.2 μl), selective antagonists of NK-1 and NK-3 receptors, respectively, were injected into the dPAG. Injection of spantide had antiaversive effects as determined by stimulation of the dPAG in naive animals and in animals subjected previously to CFC. SB 222200 also increased these aversive thresholds but only at doses that caused a motor deficit. Moreover, neither spantide nor SB 222200 influenced the PSF. The results suggest that NK-1 receptors are mainly involved in the mediation of the defensive behaviors organized in the dPAG. Because dPAG-evoked PSF was not affected by intra-dPAG injections of either spantide or SB 222200, it is suggested that neurokinin-mediated mechanisms are not involved in the processing of ascending aversive information from the dPAG.

Tibial motor nerve conduction studies: An investigation into the mechanism for amplitude drop of the proximal evoked response

The amplitude of the compound muscle action potential (CMAP) of abductor hallucis (AH) shows the largest drop with proximal stimulation of any routinely studied motor nerves. The cause has not been established. Four experiments of tibial motor nerve conduction in several healthy control subjects were performed using far-field recordings, collision, H-reflex, and intramuscular recordings of foot muscles. The proximal CMAP showed a mean peak-peak amplitude of 66% (range 57-79%) compared with the distal response. Collision and H-reflex recordings in AH did not show evidence of a contribution from the tibial-innervated calf muscle. Needle electrode recordings of CMAPs showed consistently different latencies between different foot muscles. Our experiments indicate that temporal dispersion and phase cancellation between the distal tibial-innervated foot muscles recorded by the E2 (i.e., reference) electrode can explain the drop in amplitude between the proximal and distal tibial evoked CMAP.

Somatosensory evoked potential from S1 nerve root stimulation

The objective of this study was to detect cerebral potentials elicited by proximal stimulation of the first sacral (S1) nerve root at the S1 dorsal foramen and to investigate latency and amplitude of the first cerebral potential. Tibial nerve SEP and S1 nerve root SEP were obtained from 20 healthy subjects and 5 patients with unilateral sciatic nerve or tibial nerve injury. Stimulation of the S1 nerve root was performed by a needle electrode via the S1 dorsal foramen. Cerebral potentials were recorded twice to document reproducibility. Latencies and amplitudes of the first cerebral potentials were recorded. Reproducible cerebral evoked potentials were recorded and P20s were identified in 36 of 40 limbs in the healthy subjects. The mean latency of P20 was 19.8 ± 1.6 ms. The mean amplitude of P20-N30 was 1.2 ± 0.9 μV. In the five patients, P40 of tibial nerve SEP was absent, while well-defined cerebral potentials of S1 nerve root SEP were recorded and P20 was identified from the involved side. This method may be useful in detecting S1 nerve root lesion and other disorders affecting the proximal portions of somatosensory pathway. Combined with tibial nerve SEP, it may provide useful information for diagnosis of lesions affecting the peripheral nerve versus the central portion of somatosensory pathway.

Effect of Autonomic Modulation on Human Esophageal Pain Hypersensitivity

Introduction Patients with Functional Gastrointestinal Disorders (FGID) often display persistent and heightened pain sensitivity to experimental gut stimulation, a phenomenon known as Visceral Pain Hypersensitivity (VPH). Current management of pain in FGID involves the use of either antispasmodics or antidepressants; both are often unsatisfactory. The role of the autonomic nervous system (ANS) in modulating pain is well known; however, the effect of ANS modulation on VPH has not been studied. Methods The aim was to determine whether physiological modulation of the Autonomic Nervous System (ANS) influences the degree of oeosophageal VPH in healthy volunteers using a validated model.10 healthy volunteers (avr age 30.5 years; 8 male, 6 w-British) underwent psychological profiling for stress, anxiety and personality type. Study 1 : Pain thresholds to proximal and distal oesophageal electrical stimulation were measured. Thereafter the subjects underwent hydrochloric acid infusion (0.15 M) in the distal oesophagus for 30 min. This was followed by measurements of oesophageal pain threshold (using visual analogue scales) to electrical stimulation in the proximal, unexposed oesophagus at 30, 60 and 90 min. Study 2 was performed at an interval of 2 weeks and the protocol was identical to that of study 1 except that during the acid infusion cardiac vagal tone(CVT) was increased by deep breathing at full inspiratory capacity in 4 sec followed by forced expiratory vital capacity in 6 sec at a frequency of 0.1 Hz (6 breaths/minute, over 5 min). ANS was monitored throughout in both studies. Results The majority of volunteers were ‘agreeable extroverts’, which are protective personality factors. There was only 10% depression and 20% anxiety, showing our exclusion criteria effective. 70% of the subjects rated significant for alexithymia and showed a weak non-significant correlation with the level of sensitisation to acid (r = 0.49 p = 0.14). In study 1 in comparison to baseline, we observed a reduction in CVT during acid exposure while in study 2 the CVT increased during acid exposure, that is, (study 1 difference of -0.09 vs baseline; study 2 difference of 4.93 vs baseline) (p = 0.006). In study 2, all 10 volunteers reduced their level of oesophageal sensitisation to acid in comparison to study 1 with 50% failing to sensitise completely. Overall there was a reduction in sensitisation of 16 mA between study 1 and 2 (p = 0.004). Conclusion This preliminary study suggests that the parasympathetic nervous system has anti-hyperalgesic properties in human oesophageal VPH. This data points to a possible change in the way we treat visceral pain, highlighting likely new targets for the development of novel treatments. Further research is now required with a powered study focusing on exploring mechanism of desensitisation during deep breathing.

Effect of autonomic modulation on human oesophageal pain hypersensitivity

<h3>Introduction</h3> Patients with Functional Gastrointestinal Disorders (FGID) often display persistent and heightened pain sensitivity to experimental gut stimulation, a phenomenon known as Visceral Pain Hypersensitivity (VPH). Current management of pain in FGID involves the use of either antispasmodics or antidepressants; both are often unsatisfactory. The role of the autonomic nervous system (ANS) in modulating pain is well known; however, the effect of ANS modulation on VPH has not been studied. <h3>Methods</h3> The aim was to determine whether physiological modulation of the Autonomic Nervous System (ANS) influences the degree of oeosophageal VPH in healthy volunteers using a validated model.10 healthy volunteers (avr age 30.5 years; 8 male, 6 w-British) underwent psychological profiling for stress, anxiety and personality type. <i>Study 1</i>: Pain thresholds to proximal and distal oesophageal electrical stimulation were measured. Thereafter the subjects underwent hydrochloric acid infusion (0.15 M) in the distal oesophagus for 30 min. This was followed by measurements of oesophageal pain threshold (using visual analogue scales) to electrical stimulation in the proximal, unexposed oesophagus at 30, 60 and 90 min. Study 2 was performed at an interval of 2 weeks and the protocol was identical to that of study 1 except that during the acid infusion cardiac vagal tone(CVT) was increased by deep breathing at full inspiratory capacity in 4 sec followed by forced expiratory vital capacity in 6 sec at a frequency of 0.1 Hz (6 breaths/minute, over 5 min). ANS was monitored throughout in both studies. <h3>Results</h3> The majority of volunteers were ‘agreeable extroverts’, which are protective personality factors. There was only 10% depression and 20% anxiety, showing our exclusion criteria effective. 70% of the subjects rated significant for alexithymia and showed a weak non-significant correlation with the level of sensitisation to acid (r = 0.49 p = 0.14). In study 1 in comparison to baseline, we observed a reduction in CVT during acid exposure while in study 2 the CVT increased during acid exposure, that is, (study 1 difference of -0.09 vs baseline; study 2 difference of 4.93 vs baseline) (p = 0.006). In study 2, all 10 volunteers reduced their level of oesophageal sensitisation to acid in comparison to study 1 with 50% failing to sensitise completely. Overall there was a reduction in sensitisation of 16 mA between study 1 and 2 (p = 0.004). <h3>Conclusion</h3> This preliminary study suggests that the parasympathetic nervous system has anti-hyperalgesic properties in human oesophageal VPH. This data points to a possible change in the way we treat visceral pain, highlighting likely new targets for the development of novel treatments. Further research is now required with a powered study focusing on exploring mechanism of desensitisation during deep breathing.

Sustained Enzymatic Correction by rAAV-Mediated Liver Gene Therapy Protects Against Induced Motor Neuropathy in Acute Porphyria Mice

Acute intermittent porphyria (AIP) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (PBGD) activity. Clinical features are acute neurovisceral attacks accompanied by overproduction of porphyrin precursors in the liver. Recurrent life-threatening attacks can be cured only by liver transplantation. We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven by a liver-specific promoter to provide sustained protection against induced attacks in a predictive model for AIP. Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve. Hepatocyte transduction showed no gender variation after rAAV2/8 injection, while rAAV2/5 showed lower transduction efficiency in females than males. Full protection against induced phenobarbital-attacks was achieved in animals showing over 10% of hepatocytes expressing high amounts of PBGD. More importantly, sustained hepatic expression of hPBGD protected against loss of large-caliber axons in the sciatic nerve and disturbances in nerve conduction velocity as induced by recurrent phenobarbital administrations. These data show for the first time that porphyrin precursors generated in the liver interfere with motor function. rAAV2/5-hPBGD vector can be produced in sufficient quantity for an intended gene therapy trial in patients with recurrent life-threatening porphyria attacks.

Multiple Pudendal Sensory Pathways Reflexly Modulate Bladder and Urethral Activity in Patients With Spinal Cord Injury

Electrical stimulation of pudendal afferents can evoke reflex bladder contractions with relaxation of the external urethral sphincter in cats. This voiding reflex is mediated by pudendal sensory fibers innervating the penile and prostatic urethra that engage spinal and spinobulbospinal micturition pathways, respectively. However, clinical translation of this potential therapy in individuals with spinal cord injury is limited by the lack of evidence showing analogous reflex mechanisms in humans. We investigated excitatory pudendal-to-bladder reflexes in 7 individuals with chronic spinal cord injury. We recorded isovolumetric bladder pressure and perineal electromyogram in response to intraurethral electrical stimulation at varying amplitudes and frequencies. Selective electrical stimulation of the proximal (29.7 ± 11.6 cm H(2)O) and distal urethral (23.3 ± 9.28 cm H(2)O) segments evoked sustained reflex bladder contractions in different subsets (3 each) of participants. In contrast, the corresponding reflex perineal electromyogram revealed a differential activation pattern between proximal and distal intraurethral stimulation (normalized electromyogram of 1.3 ± 0.2 and 0.3 ± 0.1, respectively, p <0.05). To our knowledge we report the first clinical evidence of 2 independent excitatory pudendal-to-bladder reflex pathways, which in turn differentially modulate efferent pudendal output. Each reflex mechanism involves complex interaction of multiple sensory inputs and may provide a neural substrate to restore micturition after spinal cord injury.

The self as phenotype

Self-awareness is viewed here as the phenotypic expression of an interaction between genes and the environment. Brain and behavioral development of fetuses and newborn infants are a rich source of information regarding what might constitute minimal self-awareness. Research indicates that newborns have feeling (subjective) experience. Unlike automata, they do not just sense and respond to proximal stimulations. In light of the explosive brain growth that takes place inside and outside of the womb, first signs of feeling as opposed to sensing experience are discussed. Feeling experience is considered as the necessary condition for having minimal self-awareness. Both would co-emerge in development. However, minimal self-awareness is rapidly supplemented with an awareness that is not just perceptual, but also conceptual and ethical, primarily defined in relation to and by others.

Patient tolerance of neuromuscular electrical stimulation (NMES) in the presence of orthopaedic implants

Neuromuscular electrical stimulation (NMES) may help reduce the incidence of deep vein thrombosis (DVT) in the postoperative total hip and knee arthroplasty patient. However, discomfort associated with stimulus may reduce patient acceptance of NMES as therapy. The aim of this study was to determine if patient comfort and tolerance of NMES was affected by applying stimulation in proximity to an orthopaedic implant. There was a concern that this may cause a concentration of current around the metal which could result in hypersensitivity of NMES and reduce its effectiveness. Twenty patients took part in this study, 10 total hip and 10 total knee arthroplasty patients. Each patient was at least 3 weeks post surgery. NMES was applied to the calf muscles of each leg using skin surface electrodes. Four excitatory levels were recorded, which were: sensory threshold, motor threshold, pain threshold and pain tolerance. Following this, patients underwent a 5 min stimulation session and indicated their overall comfort level on a visual analogue scale. Measurements of peak venous velocity, mean velocity and volume flow were recorded by duplex scanning from the popliteal vein at rest and in response to NMES elicited contractions during this session. Finally, patients completed a short verbal interview detailing their experience with the NMES treatment. The blood flow results showed increases in peak venous velocities, mean velocities and volume flow produced by NMES of 200%, 60% and 60% respectively when compared to resting blood flow. Comfort assessment indicated that the presence of a metallic implant did not give rise to hypersensitivity due to NMES. Patients found the application of calf muscle NMES comfortable and acceptable as a treatment. We conclude that the use of NMES on postoperative orthopaedic patients can be safely administered as a DVT prevention method.

Regional differences in ulnar nerve excitability may predispose to the development of entrapment neuropathy

Objective To assess whether there are differences in nerve excitability properties between proximal and distal stimulation sites in the ulnar nerve in healthy controls, which may provide information on whether alteration in ion channel function predisposes to the development of ulnar neuropathy at the elbow. Methods Nerve excitability studies were undertaken in 11 healthy controls. Studies were undertaken with stimulation of the ulnar nerve at the elbow and wrist. Recordings were obtained from abductor digiti minimi in both sets of studies. Results Recordings obtained following stimulation of the nerve at the elbow demonstrated significant differences to those obtained following stimulation of the nerve at the wrist. Specifically, there was a left shift in stimulus–response curves at the elbow compared to the wrist, with prolonged strength-duration time constant, and reduced rheobase ( P < 0.05). These changes were accompanied by increased refractoriness and reductions in superexcitability and late subexcitability ( P < 0.05). Conclusions The present findings may suggest relative depolarization of ulnar nerve axons at the elbow. Significance These changes may reflect regional differences in axonal Na +/K + pump function and thereby predispose the ulnar nerve to conduction failure and axonal degeneration when exposed to trauma.