Epidural Recordings Research Articles

Flexible, all-polymer microelectrode arrays for the capture of cardiac and neuronal signals

Microelectrode electrophysiology has become a widespread technique for the extracellular recording of bioelectrical signals. To date, electrodes are made of metals or inorganic semiconductors, or hybrids thereof. We demonstrate that these traditional conductors can be completely substituted by highly flexible electroconductive polymers. Pursuing a two-level replica-forming strategy, conductive areas for electrodes, leads and contact pads are defined as microchannels in poly(dimethylsiloxane) (PDMS) as a plastic carrier and track insulation material. These channels are coated by films of organic conductors such as polystyrenesulfonate-doped poly(3,4-ethylenedioxy-thiophene) (PEDOT:PSS) or filled with a graphite-PDMS (gPDMS) composite, either alone or in combination. The bendable, somewhat stretchable, non-cytotoxic and biostable all-polymer microelectrode arrays ( polyMEAs) with a thickness below 500 μm and up to 60 electrodes reliably capture action potentials (APs) and local field potentials (LFPs) from acute preparations of heart muscle cells and retinal whole mounts, in vivo epicortical and epidural recordings as well as during long-term in vitro recordings from cortico-hippocampal co-cultures.

Influence of current direction in transcranial magnetic stimulation (TMS) on MEP amplitude and latency – opportunity of I wave specific evaluation and stimulation

Introduction: It has been shown from invasive epidural recordings that in transcranial magnetic stimulation (TMS) a current in the brain flowing from a posterior to an anterior (p.a.) direction mainly evokes I1, I2 and I3 waves whereas a current flowing from an anterior to a posterior direction mainly evokes I3 waves. This leads to the hypotheses that in p.a. current direction the motor threshold (MT) is lower, motor evoked potentials (MEPs) are higher and latency is shorter than in a.p. direction. The aim of this study was to re-evaluate the inconsistent results in literature by means of a stimulation technique that enabled us to change the current direction without turning the coil. Methods: We investigated n=23 healthy subjects (female: n=12; mean age: 26.2±1.9 years). We recorded the MT, MEP amplitude to target 400µV (SI400µV), MT adapted IO curves and maximum stimulator output (MSO) adapted IO curves in a.p. and p.a. current direction (monophasic waveform) with the P-Stim 160 stimulator (Mag and More, Germany). Results: MT was significantly lower (p=0.003), MEP amplitudes (SI400µV) were significantly higher (p<0.001) and latencies significantly shorter (p<0.001) in p.a. current direction. RmANOVA revealed a significant influence of current direction in MSO adapted IO curves on both, MEP amplitude and latency. We observed a significant influence of current direction on latencies in MT adapted recording of IO-curves but not on MEP amplitudes. Discussion: Our results consistently demonstrate for the first time a significant influence of current direction on MT, MEP amplitude and latency at fixed stimulus intensities as well as in IO curves due to the hypotheses generated from the specific I-wave pattern. The high consistency of the results when changing the current direction without altering coil position offers the opportunity of I wave specific evaluation and stimulation in TMS.

A model of the contribution of late I-waves to α-motoneuronal activation: implications for paired-pulse TMS

In paired-pulse (conditioned-test) transcranial magnetic stimulation (TMS) protocols, the effect of the conditioning pulse on the test response can be substantial. Epidural recordings indicate that this is mediated through modulation of late indirect (I-) wave volleys. It is not well understood how strong effect sizes could arise from the later, and usually weaker, I-wave volleys. To formulate a model of I-wave summation at the spinal level to explore the contribution of late I-waves to the activation of the α-motoneuronal pool and to paired-pulse TMS measures of intracortical inhibition and facilitation. I-wave recruitment curves were modeled for the first three I-waves. A series of steps converted I-wave inputs to α-motoneuronal activation. The role of I₃ in activating the α-motoneuronal pool was investigated by manipulating the amplitude of the I₃ volley. For all TMS intensities, I₃ made a contribution to the firing of the α-motoneuronal pool that was disproportional to its contribution to the descending volley. At its most influential, I₃ increased the descending volley by 23.5% but increased the proportion of motoneurons that fired by 567%. There was a U-like relationship to stimulus intensity with inhibition of I₃, and an inverted-U relationship for facilitation of I₃, in keeping with empirical observation. Changes in spinal excitability disproportionally influenced α-motoneuronal recruitment. Late I-waves have a pivotal role in determining the response to paired-pulse TMS. The spinal transfer function that converts I-wave input to α-motoneuron activation can amplify the role of late I-waves and potentially influence paired-pulse TMS measures of intracortical inhibition and facilitation.

Integrated Double-Sided Neural Sensor With Dry-Etch BCB

This paper presents a novel structure for a neural sensor using a surface micromachining technique with dry-etch benzocyclobutene selected as the substrate and packaging material. The finished device has intracortical recording sites on both sides and epidural recording sites on the front. The design doubled the total channel number of recording sites compared with the conventional single-sided electrode structure. The developed process shows reliable, high fabrication yield, and preliminary fabrication and impedance test results suggest that this newly developed neural sensor could improve the performance and efficiency of neural recording.

Optimal spacing of surface electrode arrays for brain–machine interface applications

Brain–machine interfaces (BMIs) use signals recorded directly from the brain to control an external device, such as a computer cursor or a prosthetic limb. These control signals have been recorded from different levels of the brain, from field potentials at the scalp or cortical surface to single neuron action potentials. At present, the more invasive recordings have better signal quality, but also lower stability over time. Recently, subdural field potentials have been proposed as a stable, good quality source of control signals, with the potential for higher spatial and temporal bandwidth than EEG. Here we used finite element modeling in rats and humans and spatial spectral analysis in rats to compare the spatial resolution of signals recorded epidurally (outside the dura), with those recorded from subdural and scalp locations. Resolution of epidural and subdural signals was very similar in rats and somewhat less so in human models. Both were substantially better than signals recorded at the scalp. Resolution of epidural and subdural signals in humans was much more similar when the cerebrospinal fluid layer thickness was reduced. This suggests that the less invasive epidural recordings may yield signals of similar quality to subdural recordings, and hence may be more attractive as a source of control signals for BMIs.

Epidural and foramen‐ovale electrodes in the diagnostic evaluation of patients considered for epilepsy surgery

To evaluate the clinical utility of epidural and foramen-ovale recordings and associated morbidity in the pre-surgical evaluation of epilepsy. We retrospectively analysed 59 epilepsy patients, who underwent recordings with epidural (n = 59) and foramen-ovale electrodes (n = 46) as part of their pre-surgical evaluation between 1990-1999. The epidural and foramen-ovale evaluation was based on the results of the non-invasive EEG-video recordings in patients, in whom non-invasive evaluation failed to localise seizure onset (75%, 44 patients) or where EEG, and imaging studies were discrepant (25%, 15 patients) but allowed a testable hypothesis on the seizure onset zone. Most patients (n = 57) were evaluated between 1990-1994. Only two patients were evaluated later. The results of the epidural (n = 559) and foramen-ovale (n = 83) electrode recordings allowed us to proceed to resective epilepsy surgery in 31% (n = 18) and to exclude further invasive evaluation in 15% (n = 9) of the patients. In 49% (n = 29) of the patients the results guided further invasive recordings using subdural and/or depth electrodes. For only three patients no additional information was gained by the electrode recordings. Temporary morbidity included local infection (epidural; n = 1) and facial pain (foramen ovale; n = 1) but no permanent complication occurred. Epidural and foramen-ovale electrodes have almost been abandoned in recent years, most likely because of the improvement of neuroimaging techniques such as MRI, PET and ictal SPECT. However, in selected patients, epidural electrodes and foramen-ovale electrodes are either useful as a measure to avoid invasive evaluation or serve to guide invasive evaluation.

Influence of current direction in transcranial magnetic stimulation (TMS) on MEP amplitude and latency – opportunity of I wave specific evaluation and stimulation

Introduction: It has been shown from invasive epidural recordings that in transcranial magnetic stimulation (TMS) a current in the brain flowing from a posterior to an anterior (p.a.) direction mainly evokes I1, I2 and I3 waves whereas a current flowing from an anterior to a posterior direction mainly evokes I3 waves. This leads to the hypotheses that in p.a. current direction the motor threshold (MT) is lower, motor evoked potentials (MEPs) are higher and latency is shorter than in a.p. direction. The aim of this study was to re-evaluate the inconsistent results in literature by means of a stimulation technique that enabled us to change the current direction without turning the coil. Methods: We investigated n=23 healthy subjects (female: n=12; mean age: 26.2±1.9 years). We recorded the MT, MEP amplitude to target 400µV (SI400µV), MT adapted IO curves and maximum stimulator output (MSO) adapted IO curves in a.p. and p.a. current direction (monophasic waveform) with the P-Stim 160 stimulator (Mag and More, Germany). Results: MT was significantly lower (p=0.003), MEP amplitudes (SI400µV) were significantly higher (p<0.001) and latencies significantly shorter (p<0.001) in p.a. current direction. RmANOVA revealed a significant influence of current direction in MSO adapted IO curves on both, MEP amplitude and latency. We observed a significant influence of current direction on latencies in MT adapted recording of IO-curves but not on MEP amplitudes. Discussion: Our results consistently demonstrate for the first time a significant influence of current direction on MT, MEP amplitude and latency at fixed stimulus intensities as well as in IO curves due to the hypotheses generated from the specific I-wave pattern. The high consistency of the results when changing the current direction without altering coil position offers the opportunity of I wave specific evaluation and stimulation in TMS.

Neurophysiological Monitoring of S1 Root Function During Microsurgical Posterior Discectomy Using H-Reflex and Spinal Nerve Root Potentials

Tibial H-reflex and epidural recordings of the spinal nerve root potentials (SRP) of the S1 root were performed intermittently during microsurgical posterior discectomy. To obtain reversible conduction dysfunction of dynamically retracted spinal nerve root S1 in an on-line manner to control the surgical manipulation and prevent iatrogenic root injury. Excessive force and duration of nerve root retraction during posterior lumbar discectomy may result in additional nerve root injury and battered root syndrome. The S1 root was exposed by fenestration and the epidural electrodes were placed along the root above and below the compression site in 12 patients. H wave and SRP changes were recorded intermittently during discectomy and related to different manipulative phases of surgery. The desynchronisation index of SRP was computed off-line as a ratio between a/b, where a represents the positive deflection of the signal from the zero line and b represents peak-to-peak amplitude. The reflex muscle evoked potential from the soleus muscle (H wave), SRP1 (ascendant) and SRP2 (descendant volley) paralleled the surgical manipulation. The amplitude of the H wave significantly decreased and the desychronisation index of SRP1 (later evaluated in 8/12 patients) significantly increased after mobilization of the root with a dissector and in the late phase of intervertebral disc evacuation (P < 0.001), indicating conduction dysfunction related to surgical manipulation of the root. A good surgical outcome as shown by preserved Achilles tendon and H reflexes was related to the immediate return of H wave and SRP on stopping the harmful manipulation, and preservation of the H wave and SRP at the end of surgery.SRP monitoring brings up additional information concerning initial root injury and cumulative manipulative effects. The technique of dynamic nerve root retraction in posterior lumbar discectomy can therefore be made safer.

Dose and timing effect of etomidate on motor evoked potentials elicited by transcranial electric or magnetic stimulation in the monkey and baboon

Etomidate has been shown to both enhance and depress the cortical amplitude of somatosensory evoked potentials (SSEP) depending on the dose used. Similar amplitude increases with etomidate and motor evoked potentials resulting from cortical magnetic (tcMMEP) and electric (tcEMEP) stimulation have not been consistent. We used a primate model to elucidate the time and dose characteristics of the effect. tcMMEP and tcEMEP were characterized during bolus injections of 0.1-1.8 mg/kg etomidate in 10 adult cynomologous monkeys during a baseline anesthesia with a continuous ketamine infusion. Responses were assessed by measuring the amplitude and onset latency of the hypothenar compound action potential response. In a second experiment the epidural and hypothenar response to tcEMEP was recorded under 0.3% isoflurane anesthesia and following intravenous injection of 0.05-0.35 mg/kg etomidate. Cortical stimulation was accomplished using a Cadwell MES-10 (tcMMEP) and Digitimer D180 (tcEMEP). The amplitude of the hypothenar muscle response was increased for tcEMEP and tcMMEP at 20 min following 0.1 mg/kg etomidate in the monkey. The amplification of the tcMMEP response was significantly greater than the tcEMEP response (1.95 + 0.62 SD vs. 1.43 + 0.68 SD, P = 0.023). Responses at higher doses were all below baseline. The tcMMEP response was significantly smaller than the tcEMEP at doses above 0.9 mg/kg (all P<0.001). The onset latency values were not significantly increased at any dose or time. The epidural recording demonstrated a large increase in the number of I waves compared to the isoflurane baseline. This study demonstrates that a low dose (0.1 mg/kg) of etomidate increases the com- pound muscle action potential (CMAP) amplitude for tcEMEP and tcMMEP in the monkey whereas higher doses decrease the amplitude. Epidural recordings demonstrate a marked increase in the number of I waves consistent with a cortical effect similar to the postulated effect that results in amplification of the cortical SSEP. This suggests the amplitude loss in the hypothenar muscles may be due to depression of the spinal cord by etomidate. The CMAP response amplification at low doses was greater in tcMMEP than tcEMEP and the depression at higher doses was more with the tcMMEP technique consistent with the greater dependence of the tcMMEP technique on synaptic activation.

Field potentials from macaque area V4 predict attention in single trials with ~100% accuracy

Event Abstract Back to Event Field potentials from macaque area V4 predict attention in single trials with ~100% accuracy David Rotermund1, Simon Neitzel2, Udo Ernst1*, Sunita Mandon2, Katja Taylor2, Yulia Smiyukha2 and Klaus Pawelzik1 1 University of Bremen, Department for Theoretical Physics, Center for Cognitive Sciences, Germany 2 University of Bremen, Department for Theoretical Neurobiology, Center for Cognitive Science, Germany Coherent oscillations and synchronous activity are suggested to play an important role in selective processing and dynamic routing of information across the primary visual cortical areas. In this contribution we show that local power spectral amplitudes and phase coherency between distant recording sites allow to distinguish almost perfectly between two attentional states in a behavioural task, thus giving strong quantitative support for a functional role of oscillatory neural dynamics. Macaque monkeys were trained to perform a delayed-match-to-sample task, in which the animals had to direct attention to one of two sequences of morphing shapes presented on a computer screen. The task was to signal the reoccurrence of the initial shape of the attended morphing sequence. Recordings of local field potentials (LFPs) were performed with an array of chronically implanted intracortical microelectrodes in one animal, and epidural recording arrays in two animals. These arrays covered parts of areas V1 and V4. We employed different stimulus sizes and configurations, ranging from 1 to 4 degrees in visual angle for the shape's diameters, and from 1 to 4 degrees visual angle in shape separation. The signals were split into their frequency components by applying a Morlet-wavelet transform. From the transformed data, we computed the phase coherency (i.e. a complex-valued scalar with amplitude <=1 and a phase difference) averaged over a time interval of 2500 ms, for every electrode pair. We then used a support vector machine (SVM) to classify the attended state (attention directed either to one or to the other sequence) from the power spectral amplitudes and mean phase differences between two recording sites. Strikingly, nearly perfect state identification (up to 99.9% correct) was possible from several pairs of electrodes in V4, mainly in the frequency bands of 48 Hz and 61 Hz. From V1-V4 electrode pairs, classification with up to 76% correct was possible. A similar performance was obtained using the spectral power of single electrodes in V4 in the Gamma frequency range. Our results show that power spectral amplitudes as well as phase differences between signals from V4 can accurately inform about the direction of attention to different locations in visual space in every single trial. This effect is robust against continuous changes of the shapes at the attended location. In addition, these findings are stable under the use of different recording techniques and various stimulus configurations, thus pointing to a key mechanism based on coherent oscillations for processing information under attention. Conference: Bernstein Conference on Computational Neuroscience, Frankfurt am Main, Germany, 30 Sep - 2 Oct, 2009. Presentation Type: Poster Presentation Topic: Information processing in neurons and networks Citation: Rotermund D, Neitzel S, Ernst U, Mandon S, Taylor K, Smiyukha Y and Pawelzik K (2009). Field potentials from macaque area V4 predict attention in single trials with ~100% accuracy. Front. Comput. Neurosci. Conference Abstract: Bernstein Conference on Computational Neuroscience. doi: 10.3389/conf.neuro.10.2009.14.068 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Aug 2009; Published Online: 26 Aug 2009. * Correspondence: Udo Ernst, University of Bremen, Department for Theoretical Physics, Center for Cognitive Sciences, Bremen, Germany, udo@neuro.uni-bremen.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers David Rotermund Simon Neitzel Udo Ernst Sunita Mandon Katja Taylor Yulia Smiyukha Klaus Pawelzik Google David Rotermund Simon Neitzel Udo Ernst Sunita Mandon Katja Taylor Yulia Smiyukha Klaus Pawelzik Google Scholar David Rotermund Simon Neitzel Udo Ernst Sunita Mandon Katja Taylor Yulia Smiyukha Klaus Pawelzik PubMed David Rotermund Simon Neitzel Udo Ernst Sunita Mandon Katja Taylor Yulia Smiyukha Klaus Pawelzik Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (TMS). When applied to motor cortex it leads to after-effects on corticospinal and corticocortical excitability that may reflect LTP/LTD-like synaptic effects. An inhibitory form of TBS (continuous, cTBS) suppresses MEPs, and spinal epidural recordings show this is due to suppression of the I1 volley evoked by TMS. Here we investigate whether the excitatory form of TBS (intermittent, iTBS) affects the same I-wave circuitry. We recorded corticospinal volleys evoked by single pulse TMS of the motor cortex before and after iTBS in three conscious patients who had an electrode implanted in the cervical epidural space for the control of pain. As in healthy subjects, iTBS increased MEPs, and this was accompanied by a significant increase in the amplitude of later I-waves, but not the I1 wave. In two of the patients we tested the excitability of the contralateral cortex and found a significant suppression of the late I-waves. The extent of the changes varied between the three patients, as did their age. To investigate whether age might be a significant contributor to the variability we examined the effect of iTBS on MEPs in 18 healthy subjects. iTBS facilitated MEPs evoked by TMS of the conditioned hemisphere and suppressed MEPs evoked by stimulation of the contralateral hemisphere. There was a slight but non-significant decline in MEP facilitation with age, suggesting that interindividual variability was more important than age in explaining our data. In a subgroup of 10 subjects we found that iTBS had no effect on the duration of the ipsilateral silent period suggesting that the reduction in contralateral MEPs was not due to an increase in ongoing transcallosal inhibition. In conclusion, iTBS affects the excitability of excitatory synaptic inputs to pyramidal tract neurones that are recruited by a TMS pulse, both in the stimulated hemisphere and in the contralateral hemisphere. However the circuits affected differ from those influenced by the inhibitory, cTBS, protocol. The implication is that cTBS and iTBS may have different therapeutic targets.

Epidural cylinder electrodes for presurgical evaluation of intractable epilepsy: technical note

Background This is a technical report describing a different technique for the insertion of epidural electrodes in the preoperative evaluation of epilepsy surgery. Our experience in 67 cases using this technique is analyzed. Methods Cylinder electrodes with multiple recording nodes spaced 1 cm apart along a Silastic core are placed into the epidural space under general anesthesia through single or multiple burr holes. We reviewed the data on 67 cases of medically intractable epilepsy requiring intracranial monitoring that had epidural cylinder electrodes placed. The electrodes were placed bilaterally or contralateral to subdural grids in 64 of the 67 cases. Continuous monitoring was performed from 1 to 3 weeks. Results This method was most useful when used bilaterally or contralateral to subdural grids. Definitive surgery was rendered in 48 of 67 cases. After monitoring, all electrodes were removed at bedside or upon return to the operating room for definitive surgery. There were no mortalities, infections, cerebrospinal fluid leaks, neurologic deficits, or electrode malfunctions. Two patients (2/67, 3%) did develop subdural hematomas early in our series after dural injury near the pterion; however, these patients did not sustain permanent deficit. Conclusions Epidural cylinders are another option for preoperative monitoring, useful for determining lobe or laterality of seizure genesis. They offer an alternate method to EPEs in cases where epidural recording is desirable. The cylinder electrodes are easy to place and can be removed without a return to the operating theater. The electrodes' minimal mass effect allows them to be safely placed bilaterally or contralateral to subdural grids. The epidural cylinders can monitor cortex with a greater density of nodes and can access regions not amenable to EPEs.

Subdural electrocorticographic and epidural electromeningiographic recording for brain machine interface

Subdural electrocorticographic and epidural electromeningiographic recording for brain machine interface

Monitoring of scoliosis surgery with epidurally recorded motor evoked potentials (D wave) revealed false results

Objective To elucidate the mechanism behind D wave amplitude changes after surgical correction of scoliosis. Methods We collected D wave and muscle MEP data from 93 patients (78 female, 15 male, age range 4–19 years, mean age 15.9 years), who underwent surgical correction of scoliosis. D waves were recorded via a catheter electrode inserted epidurally through the flavectomy. Muscle MEPs from lower limb muscles were also recorded. Muscle MEPs/D wave were elicited by short trains/single transcranial electrical stimuli. SEPs were elicited through bilateral percutaneous stimulation of the tibial nerves at the ankle and an averaged response from 100 to 200 single sweeps were recorded over the scalp at Cz’/Fz. In addition, we analyzed intraoperatively obtained X-ray images of the spine in 9 patients and preoperative spinal MRI in two of those nine. Results After surgical correction of scoliosis in 25 of 93 (27%) patients, the D wave amplitude changed by more than 20% of its baseline value. A decremental change occurred in 21 (84%) and an incremental change in 4 (16%) patients. D wave decrements of more than 50% were observed in 5 patients without significant SEP changes in any of these cases. In 9 patients, intraoperatively obtained X-rays of the spine (before and after correction of spine curvature) showed no catheter displacement. Muscle MEPs did not change and postoperative sensory-motor status was normal. In 2 patients, preoperative MRI revealed displacement of the spinal cord towards the concave side of the scoliotic curvature. Conclusions During scoliosis surgery, D wave amplitude changes should be interpreted cautiously until the definitive cause(s) of these changes are found. One possible mechanism to explain D wave changes during scoliosis correction could involve rotation of the spinal cord within the spinal canal, and the relative position of the epidural recording catheter (ERC). Rotation of the spinal cord after correction of scoliosis could introduce a new relationship between the ERC and the corticospinal tracts (CTs). Due to high incidence of false D wave amplitude changes we suggest that this methodology should not be used to assess the functional integrity of the CTs during scoliosis surgery. Significance This study provides new insight into the methodology of D wave monitoring as well as strong evidence of a high incidence of false positive results using D wave monitoring during surgical correction of scoliosis.

Epidurally recorded spinal cord evoked potentials in patients with cervical myelopathy and normal central motor conduction time measured by transcranial magnetic stimulation

ObjectiveUse epidural recording of evoked spinal cord potentials (ESCPs) to investigate the pathology of cervical spondylotic myelopathy (CSM) in patients with normal central motor conduction time (CMCT) in upper and lower limbs. MethodsA total of 75 patients with CSM were studied. All patients were examined before surgery for motor evoked potentials (MEPs) following transcranial magnetic stimulation (TMS). They were also evaluated during surgery by epidurally recorded ESCPs following stimulation of the median nerve, brain and spine. ResultsSeven patients (9%) showed normal CMCT in upper and lower limbs upon TMS examination. Only the ESCPs following median nerve stimulation (MN-ESCPs) were abnormal in these patients. In 5 of the 7 patients, a marked block in conduction of MN-ESCPs was observed at the C3-4 intervertebral level. The remaining two patients showed attenuation in the amplitude of MN-ESCPs at mid-cervical levels. ConclusionsWe present 7 cases of CSM with negative CMCT findings. From the MN-ESCP results, we surmise that the pathology of CSM with normal CMCT is due predominantly to dysfunction of sensory systems involved in the upper limbs. SignificanceExamination by TMS is useful in the diagnosis of CSM but the possibility of negative CMCT findings upon TMS must be borne in mind. Multi-functional evoked spinal cord responses demonstrate that lesions in the sensory system are the major underlying pathology.

Rapid kindling in preclinical anti-epileptic drug development: The effect of levetiracetam

Purpose This study assesses the use of the serial day Rapid Kindling with Recurrent Hippocampal Seizures (RKRHS) model in drug testing by investigating the anti-epileptic effect of levetiracetam (LEV), a novel anti-epileptic drug (AED) with a unique preclinical profile. Methods Male Wistar rats ( n = 16) were implanted with a stimulation/recording electrode unit in the right hippocampus and epidural recording electrodes. One week later, all rats received 12 stimulations each day for several consecutive days according to the serial day RKRHS protocol, until they were fully kindled. Fully kindled rats were then randomly assigned to an active ( n = 8) and a control ( n = 6) group and injected once (intraperitoneal, i.p.) with levetiracetam (54 mg/kg) or saline (0.9% NaCl, 2 ml/kg), respectively. One hour later, the rats received additional kindling stimulations, during which the effect of LEV was assessed. Results One hour following injection of LEV, mean seizure stage dropped to 1.67 ± 1.03 compared to 5 ± 0 in controls ( p < 0.05). Mean ADD was also significantly shorter in the active group than in controls; 21.16 ± 5.03 s versus 57.24 ± 8.16 s, respectively ( p < 0.05). A gradual, time-dependent decline was noted in the anti-epileptic effect of LEV but this effect stayed statistically significant at least up to 2.5 h ( p < 0.05). Conclusion LEV was demonstrated to have anti-epileptic properties in RKRHS that compared to those in traditional kindling and contrast with results from classical screening tests. RKRHS may represent a valuable and sensitive screening tool early in the drug screening process.

Implantation and testing of subretinal film electrodes in domestic pigs

By definition, an electronic subretinal visual prosthesis requires the implantation of stimulation electrodes in the subretinal space of the eye. Polyimide film electrodes with flat contacts were implanted subretinally and used for electrical stimulation in acute experiments in anaesthetised domestic pigs. In two pigs, the film electrode was inserted through a sclerostomy into the vitreous cavity and, subsequently, via a retinotomy into the subretinal space around the posterior pole (ab interno approach). In three other pigs the sclera and pigment epithelium were opened for combined ab interno and transscleral positioning of the subretinal electrode. In all cases, perfluorocarbon liquid (PFCL) was used to establish a close contact between the film electrode and the outer retina. After cranial preparations of three pigs for epidural recording of visual cortex responses, retinal stimulation was performed in one pig with a film electrode implanted ab interno and in two pigs with film electrodes implanted by the ab interno and transscleral procedure. The five subretinal implantations were carried out successfully and each polyimide film electrode tip was positioned beneath the outer retina of the posterior pole. The retina was attached to the stimulation electrode in all cases. Epidural cortical responses to light and electrical stimulation were recorded in three experiments. Initial cortical responses to Ganzfeld light and to electrical stimuli occurred about 40 and 20 ms, respectively, after stimulation onset. The stimulation threshold was approximately 100 μA and, like the cortical response amplitudes, depended both on the correspondence between retinal stimulation and cortical recording sites and on the number of stimulation electrodes used simultaneously. Our results in a domestic pig model demonstrate that polyimide film electrodes can be implanted subretinally and tested by recording cortical responses to electrical stimulation. These findings suggest that the domestic pig could be an appropriate animal model for basic testing of subretinal implants.

Implantation of Stimulation Electrodes in the Subretinal Space to Demonstrate Cortical Responses in Yucatan Minipig in the Course of Visual Prosthesis Development

Purpose During the course of the development of visual prostheses, subretinal stimulation films were implanted in micropigs in order to prove the feasibility of subretinal electrical stimulation with subsequent cortical response. One aim was to demonstrate that epidural recording of visual evoked potentials is possible in the micropig. Methods Film-bound stimulation electrode arrays were placed in the subretinal space of micropigs. This enabled the retina to be stimulated subretinally. Since conventional visual evoked potential (VEP) measuring is virtually impossible in the pig from the neurosurgical point of view, epidural recording electrode arrays were positioned over the visual cortex as permanent electrodes. Results The feasibility of temporary implantation of film-bound stimulation electrode arrays was successfully demonstrated in the micropig model. On stimulation with monopolar voltage pulses (1000 to 3000 mV), reproducible epidural VEP measurements (5 to 10 μV) were detected. Conclusions The feasibility of subretinal stimulation of the retina was demonstrated in a retinal model that is similar to the human retina. This animal model therefore offers a suitable means of studying the tolerability of stimulation situations in the course of visual prosthesis development.

Transscleral implantation and neurophysiological testing of subretinal polyimide film electrodes in the domestic pig in visual prosthesis development**The first two authors (H G Sachs and Th Schanze) contributed equally to this paper.

Loss of photoreceptor function is responsible for a variety of blinding diseases, including retinitis pigmentosa. Advances in microtechnology have led to the development of electronic visual prostheses which are currently under investigation for the treatment of human blindness. The design of a subretinal prosthesis requires that the stimulation device should be implantable in the subretinal space of the eye. Current limitations in eye surgery have to be overcome to demonstrate the feasibility of this approach and to determine basic stimulation parameters. Therefore, polyimide film-bound electrodes were implanted in the subretinal space in anaesthetized domestic pigs as a prelude to electrical stimulation in acute experiments. Eight eyes underwent surgery to demonstrate the transscleral implantability of the device. Four of the eight eyes were stimulated electrically. In these four animals the cranium was prepared for epidural recording of evoked visual cortex responses, and stimulation was performed with sequences of current impulses. All eight subretinal implantation procedures were carried out successfully with polyimide film electrodes and each electrode was implanted beneath the outer retina of the posterior pole of the operated eyes. Four eyes were used for neurophysiological testing, involving recordings of epidural cortical responses to light and electrical stimulation. A light stimulus response, which occurred 40 ms after stimulation, proved the integrity of the operated eye. The electrical stimuli occurred about 20 ms after the onset of stimulation. The stimulation threshold was approximately 100 µA. Both the threshold and the cortical responses depended on the correspondence between retinal stimulation and cortical recording sites and on the number of stimulation electrodes used simultaneously. The subretinal implantation of complex stimulation devices using the transscleral procedure with consecutive subretinal stimulation is feasible in acute experiments in an animal model approximating to the situation in humans. The domestic pig is an appropriate animal model for basic testing of subretinal implants. Animal experiments with chronically implanted devices and long-term stimulation are advisable to prepare the field for successful human experiments.

Progression from frontal-parietal to mesial-temporal epilepsy after fluid percussion injury in the rat.

We recently described an in vivo model of post-traumatic epilepsy (PTE) in the rat where chronic spontaneous recurrent seizures appear following a single episode of fluid percussion injury (FPI). PTE, studied during the first 2 months post-injury, was focal and seizures originated predominantly from the frontal-parietal neocortex at or around the injury site. However, rarer bilateral seizures originating from a different and undefined focus were also observed. To shed light on the Posttraumatic Epileptogenic mechanisms and on the generation of bilateral seizures, we studied rats up to 7 months post-injury. In vivo paired epidural and depth-electrode recordings indicated that the anterior hippocampus evolves into an epileptic focus which initiates bilateral seizures. The rate of frontal-parietal seizures remained constant over time after 2 weeks post-injury, while the rate of hippocampal seizures greatly increased over time, suggesting that different mechanisms mediate neocortical and hippocampal post-traumatic epileptogenesis. Because of different temporal evolution of these foci, the epileptic syndrome was characterized by predominant frontal-parietal seizures early after injury, but by predominant mesio-temporal seizures at later time points. Pathological analysis demonstrated progressive hippocampal and temporal cortex pathology that paralleled the increase in frequency and duration of bilateral seizures. These results demonstrate that FPI-induced frontal-parietal epilepsy (FPE) progresses to mesial-temporal lobe epilepsy (MTLE) with dual pathology. These observations establish numerous similarities between FPI-induced and human PTE and further validate it as a clinically relevant model of PTE.