A model of the mammalian optic nerve fibre based on experimental data.

Several experimental data about membrane dynamics and pharmacological sensitivities of optic nerve axons have been published. The present work summarizes these data and computer simulations have been used to develop a model of the mammalian optic nerve fibre. The ionic currents description were derived from existing membrane models and particularly from a model of the somatic retinal ganglion cell (RGC) impulse generation. However, original equations had to be modified to match experimental data, which suggests that in RGCs, axonal and somatic ion channel expression are different. The new model is consistent with recent experimental results about optic nerve axonal excitability.

Auditory motion perception activates visual motion areas in early blind subjects.

We have previously shown that some visual motion areas can be specifically recruited by auditory motion processing in blindfolded sighted subjects [Poirier, C., Collignon, O., De Volder, A.G., Renier, L., Vanlierde, A., Tranduy, D., Scheiber, C., 2005. Specific activation of V5 brain area by auditory motion processing: an fMRI study. Brain Res. Cogn. Brain Res. 25, 650-658]. The present fMRI study investigated whether auditory motion processing may recruit the same brain areas in early blind subjects. The task consisted of simultaneously determining both the nature of a sound stimulus (pure tone or complex sound) and the presence or absence of its movement. When a movement was present, blind subjects had to identify its direction. Auditory motion processing, as compared to static sound processing, activated the brain network of auditory and visual motion processing classically observed in sighted subjects. Accordingly, brain areas previously considered as specific to visual motion processing could be specifically recruited in blind people by motion stimuli presented through the auditory modality. This indicates that the occipital cortex of blind people could be organized in a modular way, as in sighted people. The similarity of these results with those we previously observed in sighted subjects suggests that occipital recruitment in blind people could be mediated by the same anatomical connections as in sighted subjects.

Creating a meaningful visual perception in blind volunteers by optic nerve stimulation.

A blind volunteer, suffering from retinitis pigmentosa, has been chronically implanted with an optic nerve visual prosthesis. Vision rehabilitation with this volunteer has concentrated on the development of a stimulation strategy according to which video camera images are converted into stimulation pulses. The aim is to convey as much information as possible about the visual scene within the limits of the device's capabilities. Pattern recognition tasks were used to assess the effectiveness of the stimulation strategy. The results demonstrate how even a relatively basic algorithm can efficiently convey useful information regarding the visual scene. By increasing the number of phosphenes used in the algorithm, better performance is observed but a longer training period is required. After a learning period, the volunteer achieved a pattern recognition score of 85% at 54 s on average per pattern. After nine evaluation sessions, when using a stimulation strategy exploiting all available phosphenes, no saturation effect has yet been observed.

Simulation of intra-orbital optic nerve electrical stimulation.

In blind subjects who still have functional retinal ganglion cells, electrical stimuli applied to the optic nerve can produce localised visual sensations. This has been demonstrated with an intracranially implanted self-sizing spiral cuff electrode, but, to avoid skull opening, intra-orbital cuff implantation is now considered. In its orbital segment, the optic nerve is surrounded by subarachnoidal cerebrospinal fluid (CSF) and dura mater. Dura mater is a tough fibrous tissue that can impede electrical stimulation. In the study, the issue of whether or not to remove the dura mater at the implantation site was addressed using simulation on numerical models. Several volume conductor models were built representing, respectively: the cuff implanted directly around the nerve; the cuff over the nerve after connective tissue encapsulated the implant; and the cuff electrode placed around the dura mater. Stimulation-induced electric potential fields were computed for these configurations using a full 3D finite elements software. Responses of fibres within the nerve were computed. A large range of dural conductivities and several CSF thicknesses were considered. In all simulated conditions, the presence of dura mater around a layer of CSF increased excitation thresholds. Selectivity performance also decreased, but was found to be independent of the CSF thickness. However, simulations showed that, if the diameter of the cuff electrode is adapted to the target nerve, the injected charge associated with activation is limited within a reasonable range. Electrical stimulation of the optic nerve with a cuff electrode implanted around the dura mater should therefore be feasible.

The societal costs and quality of life of patients suffering from bipolar disorder in the Netherlands.

OBJECTIVE: To assess the societal costs and quality of life of patients suffering from bipolar disorder in the Netherlands. METHOD: Forty persons with a lifetime diagnosis of bipolar disorder (SCID/DSM-IV) and representative for the Dutch general population were interviewed to collect data on direct (use of medical resources) and indirect (productivity losses because of absence from work and reduced efficiency at work) costs of illness. Respondents' quality of life was also assessed. Prevalence (5.2%) of bipolar disorder was used to estimate total costs. RESULTS: Total costs of bipolar disorder were estimated at US 1.83 billion dollars (total direct costs = US 454 million dollars; total indirect costs = US 1.37 billion dollars). Participants' quality-of-life scores were lower than those of the general population. CONCLUSION: The societal costs form patients suffering of bipolar disorder in the Netherlands were high, especially the indirect costs because of absence from work. The quality of life of bipolar patients was lower than the general population.

Biocompatibility of platinum-metallized silicone rubber: in vivo and in vitro evaluation.

Silicone rubber is commonly used for biomedical applications, including implanted cuff electrodes for both recording and stimulation of peripheral nerves. This study was undertaken to evaluate the consequences of a new platinum metallization method on the biocompatibility of silicone rubber cuff electrodes. This method was introduced in order to allow the manufacture of spiral nerve cuff electrodes with a large number of contacts. The metallization process, implying silicone coating with poly(methyl methacrylate) (PMMA), its activation by an excimer laser and subsequent electroless metal deposition, led to a new surface microtexture. The neutral red cytotoxicity assay procedure was first applied in vitro on BALB/c 3T3 fibroblasts in order to analyze the cellular response elicited by the studied material. An in vivo assay was then performed to investigate the tissue reaction after chronic subcutaneous implantation of the metallized material. Results demonstrate that silicone rubber biocompatibility is not altered by the new platinum metallization method.

Vision rehabilitation with the optic nerve visual prosthesis.

A blind volunteer with retinitis pigmentosa has been chronically implanted with an optic nerve visual prosthesis. The axons of retinal ganglion cells have been successfully activated by electrical stimuli to evoke many distinct phosphenes over a large portion of the visual field. No sensations other than visual have been elicited. Controlled electrical stimulation of the optic nerve proved able to convey visual information useful for the localization and discrimination of objects.

The microsystems based visual prosthesis for optic nerve stimulation.

The microsystems based visual prosthesis (MiViP) visual prosthesis generates visual perceptions well below safety and stimulator saturation limits. These perceptions, called phosphenes, are of reasonably small size and are broadly distributed in the visual field. They can thus be used to convey useful visual information. Psychophysical evaluations are being performed in order to assess the implantee's benefits in the use of the MiViP optic nerve visual prosthesis. In a pattern-recognition task, the performance improved regularly with practice with an increasing score and a decreasing delay to recognition. These observations open the way toward an evaluation of general mobility improvement with the portable system. In conclusion, the results obtained so far still support the potential usefulness of the optic nerve visual prosthesis. A low-resolution artificial vision can be expected from the prosthesis after extensive training.

Occipital activation by pattern recognition in the early blind using auditory substitution for vision.

This PET study aimed at investigating the neural structures involved in pattern recognition in early blind subjects using sensory substitution equipment (SSE). Six early blind and six blindfolded sighted subjects were studied during three auditory processing tasks: a detection task with noise stimuli, a detection task with familiar sounds, and a pattern recognition task using the SSE. The results showed a differential activation pattern with the SSE as a function of the visual experience: in addition to the regions involved in the recognition process in sighted control subjects, occipital areas of early blind subjects were also activated. The occipital activation was more important when the early blind subjects used SSE than during the other auditory tasks. These results suggest that activity of the extrastriate visual cortex of early blind subjects can be modulated and bring additional evidence that early visual deprivation leads to cross-modal cerebral reorganization.

Neural morphological effects of long-term implantation of the self-sizing spiral cuff nerve electrode.

The paper reports on the histological effects of chronic implantation of self-sizing spiral cuff nerve electrodes on the cat sciatic nerve. The implantation period is about 4.4 months. Four different experimental conditions are evaluated: control, sham, bare cuff (cuffs without contacts and leads) and full cuff. The total number of axons in the nerves of the control group is compared with the three other groups. The surface occupied by collagen fibres in the nerve section, perineurium thickness, fibre diameter and myelin thickness are also measured. The average number of axons in the control nerves is found to be 16,416 (+/- 1,509) and does not differ significantly from the three other groups (p > 0.1). Collagen measurements show an extrafascicular epineurial fibrosis in the two implanted groups that is found to be significantly different (p < 0.05). No differences are encountered in the perineurium thickness analysis. Fibre diameter distributions show a regular bimodal pattern for all groups. Centrality (mean and Pm) and dispersion statistics (P25 and P75) extracted from fibre diameter distributions do not reveal significant differences. Myelin thickness distributions are also similar for all groups, as well as centrality and dispersion statistics. The present morphometrical results suggest that the effects produced by a chronic spiral cuff implant on this animal model are negligible.

Electrical stimulation of anterior visual pathways in retinitis pigmentosa.

PURPOSE: To explore electrically induced phosphenes in blind patients with retinitis pigmentosa (RP) in comparison with healthy subjects and to develop a screening test for candidates for an optic nerve visual prosthesis implantation. METHODS: Phosphenes are obtained by charge balanced biphasic pulse stimulations through a surface cathode over the closed eyelids and an anode near the opposite ear. The resulting strength-duration relationship for somatosensory, phosphene, and pain threshold has been recorded in five RP patients as well as in 10 healthy volunteers. RESULTS: In sighted subjects, the average rheobase and chronaxy for phosphene perception are 0.28 mA and 3.07 msec, respectively. For pulse durations longer than 2 msec, phosphenes are usually obtained at current strengths below the level giving rise to any other electrically generated sensation. In RP patients, however, phosphenes are not so easily obtained. One in five had no visual response at all. Another patient reported a flash perception for the longest pulse durations only. Spontaneous phosphenes interfered heavily with the stimulation in a third person. Finally, despite the higher threshold, two patients displayed normally shaped strength-duration curves. CONCLUSIONS: The surface stimulation has proven harmless, adequate, and very helpful to ascertain that the optic nerve can be electrically activated in completely blind individuals. Long-duration stimulation pulses yield very low phosphene thresholds in healthy subjects. Anterior visual pathways activation requires higher currents in RP patients.

Decreased benzodiazepine receptor density in the cerebellum of early blind human subjects.

As a first approach to study the effect of early visual deprivation in the GABA-ergic inhibitory system, the distribution of benzodiazepine receptors (BZR) was accurately estimated using [11C]flumazenil ([11C]FMZ). Measurements were carried out in five subjects who became blind early in life and in five sighted control subjects. The interactions between [11C]FMZ and BZR were described using a non-linear compartmental analysis which permitted to estimate the BZR synaptic density independently of other model parameters. The distribution of BZR in the visual areas and other cortical regions of blind subjects was qualitatively and quantitatively similar to that of controls. However, the BZR density in the cerebellum was significantly lower in blind than in control subjects (P<0.01). Our findings suggest that modifications of the cerebellar neural circuitry may be concomitant to the already observed compensatory reorganization in cerebral areas of blind subjects.

[11C]flumazenil metabolite measurement in plasma is not necessary for accurate brain benzodiazepine receptor quantification.

In this work, a mathematical correction for metabolites has been validated which estimates the relative amount of [11C]flumazenil ([11C]FMZ) in the total plasma curve from the tissue kinetic data without the need for direct metabolite measurement in blood plasma samples. Kinetic data were obtained using a 90-min three-injection protocol on five normal volunteers. First, the relative amount of [11C]FMZ in plasma was modelled by a two-parameter exponential function. The parameters were estimated either directly by fitting this model to the blood plasma metabolite measurements, or indirectly from the simultaneous fitting of tissue time activity curves from several brain regions with a non-linear FMZ kinetic model. Second, the direct and indirect metabolite corrections were fixed and the FMZ compartmental parameters were determined on a regional basis in the brain. The validation was performed by comparing the regional values of benzodiazepine receptor density Bmax and equilibrium dissociation constant Kd obtained with the direct metabolite correction with those values obtained with the indirect correction. For Bmax, the correlation coefficient r2 was above 0.97 for all subjects and the slope values of the linear regression were within the interval [0.97, 1.2]. For Kd, r2 was above 0.96, and the slope values of the linear regression were within the interval [0.99, 1.1]. Simulation studies were performed in order to evaluate whether this metabolite correction method could be used in a clinical protocol where only a single [11C]FMZ injection and a linear compartmental model are used. The resulting [11C]FMZ distribution volume estimates were found to be linearly correlated with the true values, with r2=1.0 and a slope value of 1.1. The mathematical metabolite correction proved to be a feasible and reliable method to estimate the relative amount of [11C]FMZ in plasma and the compartmental model parameters for three-injection protocols. Although validation with real data is necessary, simulation results suggest that our analysis method may also be applied to single-injection protocols.

Modelling analysis of human optic nerve fibre excitation based on experimental data.

The aim of the study is to determine which of the existing myelinated mammalian nerve fibre models better fits experimental data resulting from electrical stimulation of the human optic nerve and from propagation velocity measured on primates. The macroscopic electric potential is computed in a 3D, inhomogeneous and anisotropic nerve model. The Chiu-Sweeney (CS) and the Schwarz-Wesselink (SW) membrane descriptions are then considered. Variations in parameters that are not well established (encapsulation-tissue thickness, nerve-fascicle conductivity, geometric and electrochemical fibre cable parameters) are taken into account. Results demonstrate that the SW model predictions are in better agreement with the experimental data than those of the CS model, although thresholds are still too high. When channel densities are varied, the SW model turns out to be more robust than the CS model. For a suitable leakage channel density value (about 8% of the original one), the SW model predicts a conduction velocity of 11.4 ms-1 and an excitation threshold of 0.055 mA (for 0.1 ms pulse duration), which is in very good agreement with experimental values (11 ms-1 and 0.055 mA). Potassium current in the SW model is necessary for stability. Introduction of a potassium-like current can restore stability in the CS system.

Automatic morphometry of nerve histological sections.

A method for the automatic segmentation, recognition and measurement of neuronal myelinated fibers in nerve histological sections is presented. In this method, the fiber parameters i.e. perimeter, area, position of the fiber and myelin sheath thickness are automatically computed. Obliquity of the sections may be taken into account. First, the image is thresholded to provide a coarse classification between myelin and non-myelin pixels. Next, the resulting binary image is further simplified using connected morphological operators. By applying semantic rules to the zonal graph axon candidates are identified. Those are either isolated or still connected. Then, separation of connected fibers is performed by evaluating myelin sheath thickness around each candidate area with an Euclidean distance transformation. Finally, properties of each detected fiber are computed and false positives are removed. The accuracy of the method is assessed by evaluating missed detection, false positive ratio and comparing the results to the manual procedure with sampling. In the evaluated nerve surface, a 0.9% of false positives was found, along with 6.36% of missed detections. The resulting histograms show strong correlation with those obtained by manual measure. The noise introduced by this method is significantly lower than the intrinsic sampling variability. This automatic method constitutes an original tool for morphometrical analysis.

Changes in occipital cortex activity in early blind humans using a sensory substitution device.

The purpose of this study was to investigate the neural networks involved when using an ultrasonic echolocation device, which is a substitution prosthesis for blindness through audition. Using positron emission tomography with fluorodeoxyglucose, regional brain glucose metabolism was measured in the occipital cortex of early blind subjects and blindfolded controls who were trained to use this prosthesis. All subjects were studied under two different activation conditions: (i) during an auditory control task, (ii) using the ultrasonic echolocation device in a spatial distance and direction evaluation task. Results showed that the abnormally high metabolism already observed in early blind occipital cortex at rest [C. Veraart, A.G. De Volder, M.C. Wanet-Defalque, A. Bol, C. Michel, A.M. Goffinet, Glucose utilization in human visual cortex is, respectively elevated and decreased in early versus late blindness, Brain Res. 510 (1990) 115-121.] was also present during the control task and showed a trend to further increase during the use of the ultrasonic echolocation device. This specific difference in occipital cortex activity between the two tasks was not observed in control subjects. The metabolic recruitment of the occipital cortex in early blind subjects using a substitution prosthesis could reflect a concurrent stimulation of functional cross-modal sensory connections. Given the unfamiliarity of the task, it could be interpreted as a prolonged plasticity in the occipital cortex early deprived of visual afferences.

Auditory coding of visual patterns for the blind.

Recognition tasks of simple visual patterns have been used to assess an early visual--auditory sensory-substitution system, consisting of the coupling of a rough model of the human retina with an inverse model of the cochlea, by means of a pixel-frequency relationship. The potential advantage of the device, compared with previous ones, is to give the blind the ability to both localise and recognise visual patterns. Four evaluation sessions assessed the performance of twenty-four blindfolded sighted subjects using the device. Subjects had to recognise twenty-five visual patterns, one at a time, using a head-mounted small camera and interpreting the corresponding sounds given by the device. Half the subjects were trained by means of a correction feedback procedure during ten one-hour training sessions embedded in between the evaluation sessions. Results revealed extremely successful training effects. Performance of trained subjects significantly increased with practice compared with the untrained control group. The improvement was also observed for new patterns, demonstrating a learning-process generalisation. The negative correlation observed between scores and processing time showed that the subjects' response accuracy was related to their speed. In conclusion, simple pattern recognition is possible with a fairly natural vision-to-audition coding scheme, given the possibility for the subjects to have sensory--motor interactions while using the device.

Hybrid finite elements and spectral method for computation of the electric potential generated by a nerve cuff electrode.

An original numerical method is developed to compute the 3D electric potential generated by a dot-contact cuff electrode implanted around an axisymmetrical, inhomogeneous, anisotropic nerve. The technique is based on a 2D finite-element approach coupled with a semi-analytical Fourier spectral decomposition to approximate the solution behaviour in the azymuthal direction. The method only requires a 2D FEM mesh and allows an accurate electrode description, with any number of contacts at different angular positions. Results show that the convergence of the Fourier series is very fast: typically, the relative error due to series truncation (estimated by the norm of the difference between the solution computed with M modes and the one computed with M-1 modes, normalised by the norm of the solution computed with M modes) reaches the order of 10(-3) with six spectral modes (M = 6). As a consequence, the whole algorithm has the complexity of a 2D approach.

Visual sensations produced by optic nerve stimulation using an implanted self-sizing spiral cuff electrode.

A blind volunteer with retinitis pigmentosa was chronically implanted with a self-sizing spiral cuff electrode around an optic nerve. Electrical stimuli applied to the nerve produced localized visual sensations that were broadly distributed throughout the visual field and could be varied by changing the stimulating conditions. These results demonstrate the potential for constructing a visual prosthesis, based on electrical stimulation of the optic nerve, for blind subjects who have intact retinal ganglion cells.

A real-time experimental prototype for enhancement of vision rehabilitation using auditory substitution.

The rehabilitation of blindness, using noninvasive methods, requires sensory substitution. A theoretical frame for sensory substitution has been proposed which consists of a model of the deprived sensory system connected to an inverse model of the substitutive sensory system. This paper addresses the feasibility of this conceptual model in the case of auditory substitution, and its implementation as a rough model of the retina connected to an inverse linear model of the cochlea. We have developed an experimental prototype. It aims at allowing optimization of the sensory substitution process. This prototype is based on a personal computer which is connected to a miniature head-fixed video camera and to headphones. A visual scene is captured. Image processing achieves edge detection and graded resolution. Each picture element (pixel) of the processed image is assigned a sinusoidal tone; weighted summation of these sinewaves builds up a complex auditory signal which is transduced by the headphones. On-line selection of various parameters and real-time functioning of the device allow optimization of parameters during psychophysical experimentations. Assessment of this implementation has been initiated, and has so far demonstrated prototype usefulness for pattern recognition. An integrated circuit of this system is to be developed.