Bionic Eye from the Point of View of Functional Magnetic Resonance and Electrophysiological Examination – Review

Worsening of sight and blindness remain significant problems of general healthcare worldwide. The World Health Organization (WHO) estimates that worldwide there are approximately 253 million people with impairment of sight. In 2015, 36 million were blind and 217 million had moderate to severe visual impairment. Approximately 80 % of the cases of blindness can be avoided if preventive measures are taken or if they are diagnosed and treated early [1]. Although most blind and visually impaired people live in low-income countries, it is important to note that blindness caused by eye diseases is also an important healthcare problem in Europe [2]. In the last quarter of a century, this condition has led researchers in medicine and biomedical engineering to the development of different models of visual prostheses. According to Fernandez et al., approximately 140 000 blind people in industrial countries could benefit from a bionic eye [3].


Introduction
Worsening of sight and blindness remain significant problems Approximately 80 % of the cases of blindness can be avoided if preventive measures are taken or if they are diagnosed and treated early [1]. Although most blind and visually impaired people live in low-income countries, it is important to note that blindness caused by eye diseases is also an important healthcare problem in Europe [2]. In the last quarter of a century, this condition has led researchers in medicine and biomedical engineering to the development of different models of visual prostheses. According to Fernandez et al., approximately 140 000 blind people in industrial countries could benefit from a bionic eye [3].

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Hyperpolarisation of photoreceptors during synaptic transmission causes the release of glutamate from the presynaptic part to the synaptic cleft and its subsequent binding to the receptors located on the membrane of the postsynaptic neuron [5]. The glutamate receptors are present not only in the photoreceptors but also in the horizontal and bipolar cells, as well as in the retinal ganglion cells [6]. Glutamate is bound to the receptors, which have been named based on their selective agonists. N-methyl-D-aspartate is a typical agonist for the NMDA receptors; α-amino-3-hydroxy-5-methyl-4-8 isoxazolpropionate for the AMPA receptors, and kainate for the third type -the kainate receptors. AMPA and kainate receptors are also called non-NMDA [7].
NMDA receptors represent ion channels permeable for calcium ions (Ca). Under normal membrane potential, the flow of calcium through NMDA receptors is blocked by the magnesium (Mg) ions.
This block can be eliminated by strong depolarisation [8]. Glutamate is a predominant excitation neurotransmitter in the retina and brain of mammals [9]. After induction, the post-synaptic excitation potential glutamate must instantly be removed from the synaptic cleft. In the mammalian central nervous system, glutamate is removed from the synapsis primarily by glutamate transporters, i.e. excitatory amino acid transporter (EAAT) and glutamate aspartate transporter (GLAST), as glutamate transporters to the Muller cells (MC) and glutamine synthetase (GS) as an enzyme converting glutamate to glutamine in the MCs [10,11]. In glial cells, glutamate is subsequently changed to glutamine. Glutamine no longer acts as a neurotransmitter and can thus be released back to the synapse, from which it is subsequently taken up by the presynaptic neuron that converts it back to glutamate [12].
To date, there is no evidence of the presence of an enzyme that would convert glutamate directly in the synapse [13]. Concentration of free glutamate in the synaptic cleft during synaptic transmission is about 1.1 mM, but its concentration decreases rapidly. In NMDA receptors, it disintegrates within 1.2 ms. However, glutamate dissociates more rapidly from AMPA receptors. Thus, the time course of free glutamate predicts that dissociation contributes to the breakdown of the post-synaptic flow mediated by AMPA receptors. Otherwise the voltage-gated channels would be opened [5].

Neurotransmission in the Visual Pathway -Pathology
One of the first stimuli that led us to investigate visual pathway processes was the simultaneous measurement of the pattern electroretinogram (PERG) and the pattern visual evoked potentials

Am J Biomed Sci & Res
Copy@ Lestak Jan cells, we will start to find out at which level this lesion occurred by means of the feedback processes [16][17][18][19].
There are two possibilities for recovery of the action potentials coming to the brain to the baseline values. The first is to wash out a higher amount of the neurotransmitter and the other is to leave this neurotransmitter in the synaptic cleft for a longer time. Both possibilities have been experimentally proven in glaucoma. In the vitreous humour of glaucoma eyes of experimental animals, the glutamate value (27 microM) was up to 3-fold higher than in the control group. These values are toxic both for the layer of ganglion cells and for the internal plexiform layer [20].
The GLAST and GS values were increased following increase of the IOP in rats after 3 weeks. The number of the ganglion cells 4-60 days following the increase of IOP was reduced by 6 to 44 % [21]. In addition, the glutamate transporter may begin to work in a reverse mode and transfer glutamate and sodium from the cell back to the synaptic cleft. Thus, flushed glutamate comes only in a small portion from the synaptic pouches and most of it comes from the cytosol to which it was previously drained [22]. During the longterm effects of glutamate on non-NMDA receptors, an increase of the postsynaptic potential and opening of the voltage-controlled receptors which are normally closed by magnesium (Mg) occurs, which prevents Ca from entering the cell. This process occurs in all cells with glutamate receptors. Therefore, not only retinal ganglion cells but also cells in the inner core layer and photoreceptor layer are damaged in glaucoma [23].
Excessive calcium flow into the cell through the NMDA-voltage channel may induce hypoxia, hypoglycaemia, etc. Under these conditions, the level of glutamate in the synaptic cleft remains elevated for a long time, with sustained activation of the NMDA receptors, resulting in the intracellular calcium concentrations which are cytotoxic. Hence, this process is typical not only for impairment caused by glaucoma [24]. By glutamate binding, the NMDA receptor begins to release calcium into the cell. This can have a double effect on a cell. Under physiological conditions, it can provide the signal needed for survival of the nerve cell, and by contrast, in pathological conditions, it can have an excitotoxic effect. This is because excessive activation of glutamate receptors has many detrimental effects on the cell, including reduced ability to buffer the influent calcium, produce oxygen radicals, activate nitric oxide synthesis which may lead to cytoskeletal degradation and excessive activation of calcium-dependent enzymes [25].
For these reasons, free cytosolic calcium needs to be drained, which is ensured by the mitochondria and partly by the endoplasmic reticulum. In particular, mitochondria are important for maintaining a low concentration of cytosolic calcium and their dysfunction can lead to cell death by disrupting calcium homeostasis, releasing proapoptotic factors, or increasing production of oxygen radicals [26]. Excessive production of oxygen radicals leads to the formation of oxidative stress, which causes damage to nucleic acids, proteins, lipids, and can lead to the opening of mitochondrial channels, which in turn leads to the formation of additional oxygen radicals, energetic failure and release of pro-apoptotic factors such as cytochrome c into the cytoplasm. Oxidative stress is a major factor in the pathological neuronal damage involved in both acute and chronic central nervous system damage in many neurodegenerative diseases [25].
Other pro-apoptotic factors have been found which are released by the massive entry of calcium into the cell, such as the p38 MAP kinase pathway or the c-Jun N-terminal kinase. Free cytosolic calcium can also induce apoptosis by activating calcineurin and calpain, which are calcium-dependent apoptotic proteases [27]. However, enough energy does not only decide on the mechanism of cell death, but also on whether it occurs at all, because if the energy is deficient, the concentration of glutamate that would not normally be excitotoxic can cause it. This is because neurons and glial cells removing glutamate from the synapse need sufficient energy [28][29][30]. However, neurons are not passive, and they resist excitotoxicity by several mechanisms. One of these is the removal of glutamate from the synapse and calcium from cytosol. Another mechanism is to ensure more energy to the nervous system, which is done by incorporating more glucose transporters into the membranes, or by using lactate as a source of energy. The energy crisis is signalled by, among other things, an increased amount of adenosine produced by the consumption of adenosine triphosphate. Adenosine may function as a retrograde neurotransmitter and prevent the release of additional glutamate. Thus, it acts similarly to the intracellular feedback loops which provide inhibition of a receptor, e.g. with increasing concentration of the cytosolic calcium, glutamate, and protons. A defensive hyperpolarisation of neurons occurs by means of the potassium channels, whose opening is triggered by ATP depletion or an excess of cytosolic calcium. In addition, the synthesis of antioxidative oxygen enzymes destroying the oxygen radicals which develop during excitotoxicity (Sapolsky, 2000) may be increased [31].
Whether activation of the NMDA receptor results in excitotoxicity or neuroprotection is also probably influenced by its localisation in addition to the stimulation intensity, since NMDA receptors Copy@ Lestak Jan may occur both synaptically and extrasynaptically. Activation of the synaptic NMDA receptors appears to have a predominantly neuroprotective effect, while activation of extrasynaptic NMDA receptors triggers cell death signalling pathways [32].
As mentioned above, glutamate is the major excitatory neurotransmitter in the vertebrate brain and therefore it is necessary to maintain its levels in the physiological range (9). Under normal conditions, the concentration of glutamate in the synaptic cleft may increase up to 1 mM, from which it is then taken up in milliseconds and its concentration is again reduced [5]. However, if its amount in the vicinity of the synaptic cleft cannot be reduced or is even exceeded, the neurons undergo apoptosis or necrosis [33].
Excitotoxicity as such was first described by Olney [9]. It involves excessive activation of glutamate receptors in the CNS. Glutamate neurotoxicity caused by NMDA receptor activation was suggested only in a later study [24]. After intense activation of the NMDA receptors, glutamate excess for the neurons may be toxic in several acute injuries, including stroke [34] or epilepsy [35].

The Most Common Ophthalmological Diseases for Which a Bionic Eye is Indicated
As mentioned above, any lesion of the nerve cells in the visual pathway can damage not only the cellular nerve structures located horizontally, but also vertically. Another important finding resulting from this information, as well as from the visual pathway anatomy, is that unilateral lesions also cause damage to contralateral nerve structures [36][37][38]. Therefore, it is not possible to predict the improvement of visual functions to usable values when implanting visual neuroprothesis.
As the bionic eye is most commonly indicated in patients with retinitis pigmentosa (RP)and age-related macular degeneration (AMD), we focus mainly on these two diagnostic groups. A prerequisite for the effectiveness of this system is the preservation of the integrity of the middle and inner retinal structures, the visual pathway and the subcortical and cortical centres in the brain [39].
RP is a disease that primarily affects the rods and cones and retinal pigment epithelium located beneath. The inner core and plexiform layers, ganglion cells and their fibres undergo degeneration and are replaced by gliotic tissue. These changes may be visible in the later stage of the disease [40].  eyes concurrently did not find any brain activity [43]. Functional MRI examinations were carried out on the Philips Achieva 3T TX MR system (Philips Healthcare, Eindhoven, Netherlands) with a magnetic field strength of 3 Tesla, using the blood oxygen level dependent (BOLD) contrast. A standard 32-channel head coil was used and each measurement was performed with gradient-echo echo-planar imaging sequence.

Age-related Macular Degeneration (AMD)
In AMD, the impairment of the photoreceptors (cones) causes decrease of the retinal ganglion cells. It was found that the number   The resulting correlation coefficient between the right half of the visual field and fMRI activation extent on the left was 0.667 (p< 0.05). The correlation coefficient between the left halves of the visual fields and fMRI activation on the right was 0.767 with p< 0.016 [50].
The mean value of the difference in the number of activated voxels using the BW vs. YB stimulation is 59 % for glaucoma patients while for the healthy controls it is only 2 %. Statistical maps of BW>YB and BW<YB differences for the patients and controls were thresholded at an uncorrected threshold of p=0.001 at individual level (for each subject) and the numbers of voxels were statistically compared between all groups using t-test. While the BW>YB difference between the control group and the patients differed by the statistically significant 1.606 voxels (p=0.039), no difference was found for BW<YB (p=0.18) [50]. (Table 1). Even with these experiments we have shown that with the progression of glaucoma there is an alteration of the cortical headquarters in the brain. This implies that retinal disorder, whether at the level of photoreceptors or ganglion cells, leads to damage if visual centers in the brain, particularly in PDR. This disease is most often indicated for the implantation of visual neuroprostheses.

Bionic Eye
Currently, four systems of bionic eye have received permission for launch on the European and US markets. Many others have undergone preclinical and clinical trials which reflect the established safety profile for sustained stimulation. This progress points to an effort to assist blind patients in their hopes of real and measurable aid [51]. In the last quarter of a century, attention has been paid to retinal neuroprostheses with active stimulation (with an external source of energy).
This is a small camera system, placed in glasses, that transmits Argus II was used, the visual acuity was improved to 20/1000 (0,02) [53,54]. Other epiretinal systems include the Intelligent Retinal Implant System II (IRIS II) [55][56][57], EPI-RET3 Retinal Implant System [58]. These systems can theoretically be disadvantageous, as they rule out processing of the electric voltage changes in the bipolar, horizontal and amacrine and ganglion cells. I deliberately

Am J Biomed Sci & Res
Copy@ Lestak Jan use the term "theoretically" because, as stated before, vertical damage occurs in the photoreceptor lesions Therefore, a complex processing of the electrical changes in the retina is insufficient in advanced dystrophies. A Subretinal Chip is placed between the pigment epithelium and photoreceptors. It detects light, that is then transferred to the electrical potential and this is delivered to the retinal neurons. This system includes the Boston Retinal Implant Project (BRIP) [59], Artificial Silicon Retina [60,61], Alpha IMS and AMS [39,62], Photovoltaic Retinal Implant (PRIMA) [63][64][65].

Conclusion
Pathophysiology of neurotransmission in the visual pathway does not, in theory, allow for the successful use of a bionic eye.
Therefore, the direction of development should be pointed towards a different method.

Funding
This work was supported by Charles University Prague, Czech Republic (PROGRESS Q40/07).

Availability of Data and Materials
All data generated or analysed during this study are included in this published article or are available from the corresponding author.

Ethics approval and Consent to Participate
All patients included in the present study consented to participate, and the study protocol conformed to the principles outlined in the Declaration of Helsinki within the ethic committee.