Suprathreshold Stimulation Research Articles

Occipital nerve stimulation for chronic migraine: a randomized trial on subthreshold stimulation.

Occipital nerve stimulation (ONS) may provide pain relief in migraine patients. In this double-blinded trial we investigated the significance of paresthesia and possible placebo effects. Patients already treated with ONS reporting stable treatment effect were included. "Effective stimulation," "subthreshold stimulation" and "no stimulation" were compared. Patients cycled through all three treatment groups. Outcome was measured using the visual analog scale (VAS) for pain, McGill Pain Questionnaire and SF-36. Eight patients were included, mean preoperative VAS was 8.20 ± 1.22. A significant improvement in pain was observed in favor of suprathreshold stimulation compared to subthreshold stimulation (1.98 ± 1.56 vs 5.65 ± 2.11). Pain also significantly improved under subthreshold stimulation compared to no stimulation (5.65 ± 2.11 vs 8.45 ± 0.99). No changes in SF-36 were observed. Paresthesia is not required to achieve pain reduction but suprathreshold stimulation yields better results, underlining the significance of stimulation parameter customization.

Response of human thalamic neurons to high-frequency stimulation.

Thalamic deep brain stimulation (DBS) is an effective treatment for tremor, but the mechanisms of action remain unclear. Previous studies of human thalamic neurons to noted transient rebound bursting activity followed by prolonged inhibition after cessation of high frequency extracellular stimulation, and the present study sought to identify the mechanisms underlying this response. Recordings from 13 thalamic neurons exhibiting low threshold spike (LTS) bursting to brief periods of extracellular stimulation were made during surgeries to implant DBS leads in 6 subjects with Parkinson's disease. The response immediately after cessation of stimulation included a short epoch of burst activity, followed by a prolonged period of silence before a return to LTS bursting. A computational model of a population of thalamocortical relay neurons and presynaptic axons terminating on the neurons was used to identify cellular mechanisms of the observed responses. The model included the actions of neuromodulators through inhibition of a non-pertussis toxin sensitive K+ current (IKL), activation of a pertussis toxin sensitive K+ current (IKG), and a shift in the activation curve of the hyperpolarization-activated cation current (Ih). The model replicated well the measured responses, and the prolonged inhibition was associated most strongly with changes in IKG while modulation of IKL or Ih had minimal effects on post-stimulus inhibition suggesting that neuromodulators released in response to high frequency stimulation are responsible for mediating the post-stimulation bursting and subsequent long duration silence of thalamic neurons. The modeling also indicated that the axons of the model neurons responded robustly to suprathreshold stimulation despite the inhibitory effects on the soma. The findings suggest that during DBS the axons of thalamocortical neurons are activated while the cell bodies are inhibited thus blocking the transmission of pathological signals through the network and replacing them with high frequency regular firing.

Acute prediction of laryngeal outcome during thyroid surgery by electromyographic laryngeal monitoring

The purpose of this study was to evaluate the contribution of laryngeal intraoperative nerve monitoring (IONM) during thyroidectomy in predicting postoperative laryngeal mobility. Between 2009 and 2012, 127 patients underwent thyroidectomy, during which 216 recurrent laryngeal nerves were stimulated with suprathreshold stimulations. Laryngeal mobility was examined through direct laryngoscopy. Statistical analysis was performed to determine specificity, sensitivity, negative predictive value (NPV), positive predictive value (PPV), and a threshold value in order to define a intraoperative diagnostic test. Nine patients had a unilateral laryngeal palsy. No bilateral laryngeal palsy was observed. The threshold value to assure the postoperative laryngeal mobility is 280 μV. For this value, specificity was 94.06%, sensitivity 100%, NPV 100%, and PPV 47.83%. Laryngeal IONM can predict a favorable outcome of laryngeal mobility in cases in which the response exceeds 280 μV. Under this value, the risk of palsy is about 50% suggesting a staged surgery.

12. More pulses – lower thresholds? The efficacy of the number of pulses within a stimulus train to elicit MEPs

The multipulse transcranial electrical stimulation (TES) is used intraoperatively to elicit motor evoked potentials (MEPs). In supratentorial surgeries a slightly suprathreshold stimulation is established to avoid deep white matter activation. Thus, stimulation paradigms are optimized to achieve lowest motor threshold (MT). However a systematic study on the effect of the number of pulses (NOP) on MT has not been performed and thus evaluated. In twenty-five patients (55 ± 12 y.o., 10 females, normal motor status) underwent brain surgery, the MTs of the MEPs from the 1st interosseus muscle of the hand were measured, after TES with −19 NOP. The stimulations were delivered by a constant current stimulator (maximum 220 mA) with the following montages: C-1 C2, C-1 C1, C3-Cz, C4-Cz, the interstimulus interval was 4 ms and the pulse width 0.5 ms. The thresholds of left vs right cortex stimulation, ‘affected’ vs ’unaffected’ hemisphere, stimulating montages and different NOP were compared (Student’s t-test). MEPs were elicited in 5/25 patients (20%) with NOP = 1, in 24/25 patients (96%) with NOP = 2 and in all patients with NOP ⩾ 3. There is no significant difference of the MTs between left/right hemisphere ( p > 0.5), ‘affected’/‘unaffected’ hemisphere ( p > 0.5) and stimulating montages (p > 0.5) for any number (2-9) of pulses. There is significant difference between NOP2/NOP5 (p < 0.05), but not between NOP5/NOP8 (p > 0.5). The MT averages (in mA) for −29 pulses are the following: MTNOP2: 79.3 ± 40.6, MTNOP3: 65.6 ± 26.9, MTNOP4: 60.7 ± 24.2, MTNOP5: 58.4 ± 23.2, MTNOP6: 57.0 ± 22.4, MTNOP7: 56.1 ± 21.7, MTNOP8: 55.3 ± 21.4, MTNOP9: 55.0 ± 21.4 (mean ± SD). The MT for any NOP can be well predicted (R2 = 0.9997), knowing just the MTNOP4 and MTNOP5, by the following hyperbolic equation: MT (NOPx)=0.47 ∗ MTNOP4 ∗ (NOPx-1)-b + 0. 87 ∗ MTNOP5, where b = MTNOP5/MTNOP4. This study shows that the stimulation with a train of more than five pulses does not lower efficiently the MT of the MEPs. The ‘MT-NOP’ curve can be approximated by a hyperbolic function.

How Thoughts Give Rise to Action - Conscious Motor Intention Increases the Excitability of Target-Specific Motor Circuits

The present study shows evidence for conscious motor intention in motor preparation prior to movement execution. We demonstrate that conscious motor intention of directed movement, combined with minimally supra-threshold transcranial magnetic stimulation (TMS) of the motor cortex, determines the direction and the force of resulting movements, whilst a lack of intention results in weak and omni-directed muscle activation. We investigated changes of consciously intended goal directed movements by analyzing amplitudes of motor-evoked potentials of the forearm muscle, flexor carpi radialis (FCR), and extensor carpi radialis (ECR), induced by transcranial magnetic stimulation over the right motor cortex and their motor outcome. Right-handed subjects were asked to develop a strong intention to move their left wrist (flexion or extension), without any overt motor output at the wrist, prior to brain stimulation. Our analyses of hand acceleration and electromyography showed that during the strong motor intention of wrist flexion movement, it evoked motor potential responses that were significantly larger in the FCR muscle than in the ECR, whilst the opposite was true for an extension movement. The acceleration data on flexion/extension corresponded to this finding. Under no-intention conditions again, which served as a reference for motor evoked potentials, brain stimulation resulted in undirected and minimally simultaneous extension/flexion innervation and virtually no movement. These results indicate that conscious intentions govern motor function, which in turn shows that a neuronal activation representing an “intention network” in the human brain pre-exists, and that it functionally represents target specific motor circuits. Until today, it was unclear whether conscious motor intention exists prior to movement, or whether the brain constructs such an intention after movement initiation. Our study gives evidence that motor intentions become aware before any motor execution.

Influence of Waveform and Current Direction on Short-Interval Intracortical Facilitation: A Paired-Pulse TMS Study

BackgroundTranscranial magnetic stimulation (TMS) of the human primary motor hand area (M1-HAND) can produce multiple descending volleys in fast-conducting corticospinal neurons, especially so-called indirect waves (I-waves) resulting from trans-synaptic excitation. Facilitatory interaction between these I-waves can be studied non-invasively using a paired-pulse paradigm referred to as short-interval intracortical facilitation (SICF). Objective/hypothesisWe examined whether SICF depends on waveform and current direction of the TMS pulses. MethodsIn young healthy volunteers, we applied single- and paired-pulse TMS to M1-HAND. We probed SICF by pairs of monophasic or half-sine pulses at suprathreshold stimulation intensity and inter-stimulus intervals (ISIs) between 1.0 and 5.0 ms. For monophasic paired-pulse stimulation, both pulses had either a posterior–anterior (PA) or anterior–posterior (AP) current direction (AP–AP or PA–PA), whereas current direction was reversed between first and second pulse for half-sine paired-pulse stimulation (PA–AP and AP–PA). ResultsMonophasic AP–AP stimulation resulted in stronger early SICF at 1.4 ms relative to late SICF at 2.8 and 4.4 ms, whereas monophasic PA–PA stimulation produced SICF of comparable size at all three peaks. With half-sine stimulation the third SICF peak was reduced for PA–AP current orientation compared with AP–PA. ConclusionSICF elicited using monophasic as well as half-sine pulses is affected by current direction at clearly suprathreshold intensities. The impact of current orientation is stronger for monophasic compared with half-sine pulses. The direction-specific effect of paired-pulse TMS on the strength of early versus late SICF shows that different cortical circuits mediate early and late SICF.

Histamine Modulation of Acute Nociception Involves Regulation of Nav1.8 in Primary Afferent Neurons in Mice

To explore the role of histamine in acute pain perception and its possible mechanisms. Pain-like behaviors induced by four types of noxious stimuli (hot-plate, tail-pressure, acetic acid, and formalin) were accessed in mice. Nav 1.8 expression and functions in primary afferent neurons were compared between histidine decarboxylase knockout (HDC(-/-) ) mice and their wild-types. HDC(-/-) mice, lacking in endogenous histamine, showed elevated sensitivity to all these noxious stimuli, as compared with the wild-types. In addition, a depletion of endogenous histamine with α-fluoromethylhistidine (α-FMH), a specific HDC inhibitor, or feeding mice a low-histamine diet also enhanced nociception in the wild-types. Nav 1.8 expression in primary afferent neurons was increased both in HDC(-/-) and in α-FMH-treated wild-type mice. A higher Nav 1.8 current density, a lower action potential (AP) threshold, and a higher firing rate in response to suprathreshold stimulation were observed in nociception-related small DRG neurons of HDC(-/-) mice. Nav 1.8 inhibitor A-803467, but not TTX, diminished the hyperexcitability and blocked repetitive AP firing of these neurons. Our results indicate that histamine participates in acute pain modulation in a dose-related manner. The regulation of Nav 1.8 expression and the excitability of nociceptive primary afferent neurons may be involved in the underlying mechanisms.

Glia inhibition suppresses chemotherapy-induced neuropathic pain in the rat

Oxaliplatin, a platinum-based chemotherapeutic agent, has become a standard treatment for advanced colorectal cancer. The dose-limiting toxicity of this compound is the development of a peripheral neuropathy. Recently, we described a characteristic glia activation profile in the presence of oxaliplatin-dependent neuropathic pain in the rat. In the present study, aimed to evaluate the glia role in neuropathy induced by oxaliplatin, we continuosly infused in the rat, by intrathecal route, minocycline, a tetracycline derivative that specifically inhibits microglia, or fluorocitrate, an astrocyte metabolic inhibitor of the citric acid cycle. Both compounds were able to significantly reduce oxaliplatin-dependent pain, when evaluated as an increase on suprathreshold stimulation (hyperalgesia-related measure) or as a decrease in pain threshold (allodynia-related measure) [1]. In the dorsal horn of the lumbar spinal cord minocycline was able to reduce in a time-dependent manner the Iba1 positive cell increase evoked by the anticancer treatment. Similarly fluorocitrate-treated animals showed a decreased in GFAP-positive cell with respect to the oxaliplatin-treated group. Minocycline and fluorocitrate did not show cross-action on astrocyte and microglia, respectively. The morphometric determinations performed on the DRG neurons evidenced that oxaliplatin decreased the soma area of the medium (600-1200 μm2) and large neurons (>1200 μm2) as well as the incidence of eccentric nucleoli and of multinucleolated neurons were significatively increased in oxaliplatin treated rats. Neither minocycline nor fluorocitrate were able to prevent nervous tissue alteration. In summary, these data highlight the central role of glia cell in oxaliplatin-dependent neuropathic pain. On the contrary, glia inhibition does not induce neurorestorative processes suggesting the need of glia signalling modulation to obtain at the same time pain relief and neuroprotection.

L-type CaV1.2 deletion in the cochlea but not in the brainstem reduces noise vulnerability: implication for CaV1.2-mediated control of cochlear BDNF expression

Voltage-gated L-type Ca2+ channels (L-VGCCs) like CaV1.2 are assumed to play a crucial role for controlling release of trophic peptides including brain-derived neurotrophic factor (BDNF). In the inner ear of the adult mouse, besides the well-described L-VGCC CaV1.3, CaV1.2 is also expressed. Due to lethality of constitutive CaV1.2 knock-out mice, the function of this ion channel as well as its putative relationship to BDNF in the auditory system is entirely elusive. We recently described that BDNF plays a differential role for inner hair cell (IHC) vesicles release in normal and traumatized condition. To elucidate a presumptive role of CaV1.2 during this process, two tissue-specific conditional mouse lines were generated. To distinguish the impact of CaV1.2 on the cochlea from that on feedback loops from higher auditory centers CaV1.2 was deleted, in one mouse line, under the Pax2 promoter (CaV1.2Pax2) leading to a deletion in the spiral ganglion neurons, dorsal cochlear nucleus, and inferior colliculus. In the second mouse line, the Egr2 promoter was used for deleting CaV1.2 (CaV1.2Egr2) in auditory brainstem nuclei. In both mouse lines, normal hearing threshold and equal number of IHC release sites were observed. We found a slight reduction of auditory brainstem response wave I amplitudes in the CaV1.2Pax2 mice, but not in the CaV1.2Egr2 mice. After noise exposure, CaV1.2Pax2 mice had less-pronounced hearing loss that correlated with maintenance of ribbons in IHCs and less reduced activity in auditory nerve fibers, as well as in higher brain centers at supra-threshold sound stimulation. As reduced cochlear BDNF mRNA levels were found in CaV1.2Pax2 mice, we suggest that a CaV1.2-dependent step may participate in triggering part of the beneficial and deteriorating effects of cochlear BDNF in intact systems and during noise exposure through a pathway that is independent of CaV1.2 function in efferent circuits.

Responses of Retinal Ganglion Cells to Extracellular Electrical Stimulation, from Single Cell to Population: Model-Based Analysis

Retinal ganglion cells (RGCs), which survive in large numbers following neurodegenerative diseases, could be stimulated with extracellular electric pulses to elicit artificial percepts. How do the RGCs respond to electrical stimulation at the sub-cellular level under different stimulus configurations, and how does this influence the whole-cell response? At the population level, why have experiments yielded conflicting evidence regarding the extent of passing axon activation? We addressed these questions through simulations of morphologically and biophysically detailed computational RGC models on high performance computing clusters. We conducted the analyses on both large-field RGCs and small-field midget RGCs. The latter neurons are unique to primates. We found that at the single cell level the electric potential gradient in conjunction with neuronal element excitability, rather than the electrode center location per se, determined the response threshold and latency. In addition, stimulus positioning strongly influenced the location of RGC response initiation and subsequent activity propagation through the cellular structure. These findings were robust with respect to inhomogeneous tissue resistivity perpendicular to the electrode plane. At the population level, RGC cellular structures gave rise to low threshold hotspots, which limited axonal and multi-cell activation with threshold stimuli. Finally, due to variations in neuronal element excitability over space, following supra-threshold stimulation some locations favored localized activation of multiple cells, while others favored axonal activation of cells over extended space.

Genetically Encoded Green Fluorescent Ca2+ Indicators with Improved Detectability for Neuronal Ca2+ Signals

Imaging the activities of individual neurons with genetically encoded Ca2+ indicators (GECIs) is a promising method for understanding neuronal network functions. Here, we report GECIs with improved neuronal Ca2+ signal detectability, termed G-CaMP6 and G-CaMP8. Compared to a series of existing G-CaMPs, G-CaMP6 showed fairly high sensitivity and rapid kinetics, both of which are suitable properties for detecting subtle and fast neuronal activities. G-CaMP8 showed a greater signal (F max/F min = 38) than G-CaMP6 and demonstrated kinetics similar to those of G-CaMP6. Both GECIs could detect individual spikes from pyramidal neurons of cultured hippocampal slices or acute cortical slices with 100% detection rates, demonstrating their superior performance to existing GECIs. Because G-CaMP6 showed a higher sensitivity and brighter baseline fluorescence than G-CaMP8 in a cellular environment, we applied G-CaMP6 for Ca2+ imaging of dendritic spines, the putative postsynaptic sites. By expressing a G-CaMP6-actin fusion protein for the spines in hippocampal CA3 pyramidal neurons and electrically stimulating the granule cells of the dentate gyrus, which innervate CA3 pyramidal neurons, we found that sub-threshold stimulation triggered small Ca2+ responses in a limited number of spines with a low response rate in active spines, whereas supra-threshold stimulation triggered large fluorescence responses in virtually all of the spines with a 100% activity rate.

Muscarinic Receptors in Amygdala Control Trace Fear Conditioning

Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF) is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs) and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA). The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine) or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning.

Local Loperamide Injection Reduces Mechanosensitivity of Rat Cutaneous, Nociceptive C-Fibers

Loperamide reverses signs of mechanical hypersensitivity in an animal model of neuropathic pain suggesting that peripheral opioid receptors may be suitable targets for the treatment of neuropathic pain. Since little is known about loperamide effects on the responsiveness of primary afferent nerve fibers, in vivo electrophysiological recordings from unmyelinated afferents innervating the glabrous skin of the hind paw were performed in rats with an L5 spinal nerve lesion or sham surgery. Mechanical threshold and responsiveness to suprathreshold stimulation were tested before and after loperamide (1.25, 2.5 and 5 µg in 10 µl) or vehicle injection into the cutaneous receptive field. Loperamide dose-dependently decreased mechanosensitivity in unmyelinated afferents of nerve-injured and sham animals, and this effect was not blocked by naloxone pretreatment. We then investigated loperamide effects on nerve conduction by recording compound action potentials in vitro during incubation of the sciatic nerve with increasing loperamide concentrations. Loperamide dose-dependently decreased compound action potentials of myelinated and unmyelinated fibers (ED50 = 8 and 4 µg/10 µl, respectively). This blockade was not prevented by pre-incubation with naloxone. These results suggest that loperamide reversal of behavioral signs of neuropathic pain may be mediated, at least in part, by mechanisms independent of opioid receptors, most probably by local anesthetic actions.

Effect of intermittent theta‐burst stimulation on akinesia and sensorimotor integration in patients with Parkinson’s disease

High-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) has been shown to reduce akinesia in Parkinson's disease (PD). Given that the processing of sensory afferents is deficient in PD and might be involved in akinesia, we sought to determine whether or not the application of very HF rTMS [intermittent theta-burst stimulation (iTBS) protocol] over the M1 affected sensorimotor integration (SMI) and akinesia. The experiments were carried out in: (i) 11 patients taking their usual dopaminergic treatment ('on-drug'); (ii) eight of the latter patients after withdrawal of dopaminergic treatment ('off-drug'); and (iii) 10 de novo (drug-naive) patients. Sham stimulation was applied in 11 other patients in the 'on-drug' condition. SMI was investigated by conditioning a supra-threshold transcranial magnetic stimulation pulse in the motor region controlling the abductor pollicis brevis with a nerve shock over the median nerve at time intervals corresponding to short- and long-latency afferent inhibition (SAI and LAI) and afferent-induced facilitation (AIF). Akinesia was assessed with a pointing test. In on-drug, off-drug and de novo patients, akinesia in the contralateral arm was lower after iTBS. Sham stimulation had no effect. In on-drug patients (but not other groups), SMI was also influenced by iTBS, with an increase in AIF. No changes in SAI and LAI were observed. Our data suggest that iTBS might improve both akinesia and sensory processing in patients with PD taking levodopa.

Spine Calcium Transients Induced by Synaptically-Evoked Action Potentials Can Predict Synapse Location and Establish Synaptic Democracy

CA1 pyramidal neurons receive hundreds of synaptic inputs at different distances from the soma. Distance-dependent synaptic scaling enables distal and proximal synapses to influence the somatic membrane equally, a phenomenon called “synaptic democracy”. How this is established is unclear. The backpropagating action potential (BAP) is hypothesised to provide distance-dependent information to synapses, allowing synaptic strengths to scale accordingly. Experimental measurements show that a BAP evoked by current injection at the soma causes calcium currents in the apical shaft whose amplitudes decay with distance from the soma. However, in vivo action potentials are not induced by somatic current injection but by synaptic inputs along the dendrites, which creates a different excitable state of the dendrites. Due to technical limitations, it is not possible to study experimentally whether distance information can also be provided by synaptically-evoked BAPs. Therefore we adapted a realistic morphological and electrophysiological model to measure BAP-induced voltage and calcium signals in spines after Schaffer collateral synapse stimulation. We show that peak calcium concentration is highly correlated with soma-synapse distance under a number of physiologically-realistic suprathreshold stimulation regimes and for a range of dendritic morphologies. Peak calcium levels also predicted the attenuation of the EPSP across the dendritic tree. Furthermore, we show that peak calcium can be used to set up a synaptic democracy in a homeostatic manner, whereby synapses regulate their synaptic strength on the basis of the difference between peak calcium and a uniform target value. We conclude that information derived from synaptically-generated BAPs can indicate synapse location and can subsequently be utilised to implement a synaptic democracy.

An Optimization-Based Study of Equivalent Circuit Models for Representing Recordings at the Neuron–Electrode Interface

Extracellular neuroelectronic interfacing is an emerging field with important applications in the fields of neural prosthetics, biological computation, and biosensors. Traditionally, neuron-electrode interfaces have been modeled as linear point or area contact equivalent circuits but it is now being increasingly realized that such models cannot explain the shapes and magnitudes of the observed extracellular signals. Here, results were compared and contrasted from an unprecedented optimization-based study of the point contact models for an extracellular "on-cell" neuron-patch electrode and a planar neuron-microelectrode interface. Concurrent electrophysiological recordings from a single neuron simultaneously interfaced to three distinct electrodes (intracellular, "on-cell" patch, and planar microelectrode) allowed novel insights into the mechanism of signal transduction at the neuron-electrode interface. After a systematic isolation of the nonlinear neuronal contribution to the extracellular signal, a consistent underestimation of the simulated suprathreshold extracellular signals compared to the experimentally recorded signals was observed. This conclusively demonstrated that the dynamics of the interfacial medium contribute nonlinearly to the process of signal transduction at the neuron-electrode interface. Further, an examination of the optimized model parameters for the experimental extracellular recordings from sub- and suprathreshold stimulations of the neuron-electrode junctions revealed that ionic transport at the "on-cell" neuron-patch electrode is dominated by diffusion whereas at the neuron-microelectrode interface the electric double layer (EDL) effects dominate. Based on this study, the limitations of the equivalent circuit models in their failure to account for the nonlinear EDL and ionic electrodiffusion effects occurring during signal transduction at the neuron-electrode interfaces are discussed.

Differential effects of lidocaine on nerve growth factor (NGF)‐evoked heat‐ and mechanical hyperalgesia in humans

We investigated the effects of a non-specific sodium channel blocker (lidocaine) on heat pain thresholds and mechanical impact pain at day 7 and 21 after intradermal injection of 1 μg NGF. Measurements were performed in 12 healthy male subjects prior to and 5 min after intradermal injection of 150 μl lidocaine administered at concentrations of 0.01% (∼0.4 mM) and 0.1% (∼4 mM) to both NGF and control skin sites. NGF caused a maximum reduction of heat pain thresholds at day 7 (NGF 42.6 ± 0.6 vs. 49.4 ± 0.3 °C in control skin). Lidocaine sensitized normal skin for heat pain, but reduced heat hyperalgesia after NGF at day 7 (44.3 ± 0.8 °C, lidocaine 0.1%; p < 0.005). Pain upon supra-threshold mechanical impact stimulation was increased after NGF at day 7 (VAS 29 + 5) and massively enhanced at day 21 (VAS 64 + 5, p < 0.001). Lidocaine dose-dependently attenuated mechanically-induced pain at both control and NGF-treated sites. Maximum lidocaine effects on mechanical hyperalgesia were recorded at day 21 in NGF skin (pain reduction to VAS 37 ± 4, p < 0.00001). Repetitive impact stimuli caused increasingly more pain at the NGF sites at day 21 and this pain increase was efficiently suppressed by lidocaine 0.1%. Lidocaine differentially affects NGF-induced mechanical hyperalgesia (analgesic effect) and heat sensitivity of nociceptors (sensitizing effect). These opposing responses may be attributed to block of sodium channels vs. sensitization of TRPV1. NGF-evoked extreme mechanical impact pain indicates high action potential discharge frequencies, which might be more susceptible to lidocaine block.

Evidence‐based electroconvulsive therapy

Evidence‐based electroconvulsive therapy

Electrical stimulation — a therapeutic strategy for retinal and optic nerve disease?

Since Galvani’s experiments with frog legs in 1791, we know that neural tissue can be readily excited by electrical currents. Doctors have utilized the therapeutic potential of electricity ever since, with such lasting achievements as cardioversion and defibrillation. In ophthalmology, one of the earliest scientific mentions of electrical currents is from Henri Dor in 1873 [1]. He used complicated machines for the treatment of “amblyopia and amauroses”, “retinochoroiditis with pigment infiltration”, “glaucoma”, and “white optic atrophy” — following a tendency of a technology minded era when electrical currents were praised for all kinds of ailments. His experiments and studies, however, fell into oblivion in the following decades at the beginning of the twentieth century, with giant progress of scientific medical practice in many other areas. Electrical stimulation of the visual system was re-discovered in the 1970s for elicitation of visual percepts, or phosphenes, by supra-threshold stimulation [2]. These experiments constituted the basis for retinal implants which today allow patients to recognize letters and shapes in laboratory and natural settings [3, 4]. During the course of these trials, the therapeutic potential of subthreshold electrical stimulation was detected in 2004 by Chow [5] in patients carrying an inactive subretinal prosthesis which produced only sub-threshold currents. His patients experienced amelioration of their residual vision even in retinal areas far from the implant. This effect was attributed to the release of neurotrophic factors, and various groups worldwide started to explore the therapeutic potential in animal experiments and in human trials. For practical reasons — such as ease of use and availability — application of currents through corneal electrodes has been widely adopted since then, coining the term transcorneal electrical stimulation (TES). Various types of contact lens-electrodes or DTL-electrodes deliver currents to counter-electrodes, usually integrated in the corneal electrode or on the periorbital skin, to ensure good transretinal currents. More than 20 peer-reviewed publications in PubMed in the last 5 years are evidence for this renewed interest in electrical stimulation of ocular tissue.

Small nerve fibres, small hands and small feet: a new syndrome of pain, dysautonomia and acromesomelia in a kindred with a novel NaV1.7 mutation

The Na(V)1.7 sodium channel is preferentially expressed within dorsal root ganglion and sympathetic ganglion neurons and their small-diameter peripheral axons. Gain-of-function variants of Na(V)1.7 have recently been described in patients with painful small fibre neuropathy and no other apparent cause. Here, we describe a novel syndrome of pain, dysautonomia, small hands and small feet in a kindred carrying a novel Na(V)1.7 mutation. A 35-year-old male presented with erythema and burning pain in the hands since early childhood, later disseminating to the feet, cheeks and ears. He also experienced progressive muscle cramps, profound sweating, bowel disturbances (diarrhoea or constipation), episodic dry eyes and mouth, hot flashes, and erectile dysfunction. Neurological examination was normal. Physical examination was remarkable in revealing small hands and feet (acromesomelia). Blood examination and nerve conduction studies were unremarkable. Intra-epidermal nerve fibre density was significantly reduced compared to age- and sex-matched normative values. The patient's brother and father reported similar complaints including distal extremity redness and pain, and demonstrated comparable distal limb under-development. Quantitative sensory testing revealed impaired warmth sensation in the proband, father and brother. Genetic analysis revealed a novel missense mutation in the SCN9A gene encoding sodium channel Na(V)1.7 (G856D; c.2567G > A) in all three affected subjects, but not in unaffected family members. Functional analysis demonstrated that the mutation hyperpolarizes (-9.3 mV) channel activation, depolarizes (+6.2 mV) steady-state fast-inactivation, slows deactivation and enhances persistent current and the response to slow ramp stimuli by 10- to 11-fold compared with wild-type Na(V)1.7 channels. Current-clamp analysis of dorsal root ganglion neurons transfected with G856D mutant channels demonstrated depolarized resting potential, reduced current threshold, increased repetitive firing in response to suprathreshold stimulation and increased spontaneous firing. Our results demonstrate that the G856D mutation produces DRG neuron hyperexcitability which underlies pain in this kindred, and suggest that small peripheral nerve fibre dysfunction due to this mutation may have contributed to distal limb under-development in this novel syndrome.