# Sensory Systems/Neurosensory Implants/Future Directions/Optogenetics
### Photostimulation of neurons

Photo-stimulation of neurons is an emerging field of research. Neuronal firing is achieved by shining a focused light source onto the nerve cell, causing it to depolarize. There are two major ways to approach this goal: irradiation of the neurons with a laser, inducing a local temperature gradient; and the introduction of light sensitive channels or receptors into the nerve cell making it sensitive to light, similar to rods and cones in the human retina. Advantages over the traditionally used electric stimulation are increased precision and less to no tissue trauma.

#### Electric vs Optic stimulation

Electric stimulation has inherent limitations compared to optic stimulation. To elicit reliable firing the electrodes have to be in physical contact with or in close proximity to the targeted tissue. Introduction of electrodes into the nerve tissue damages it and surrounding tissue.
In many cases the electrode array is introduced into electrically conductive tissue allowing for current spread, further decreasing the spacial resolution that can be achieved.
Measurement of the evoked neural activity is often contaminated by stimulation artefacts much larger than the measured neural activity. This is especially the case in measurements close to the excitation site.
In contrast, optic stimulation can reliably achieve excitation of single cells or small cell populations. It does not require direct contact to the target tissue, reducing tissue damage. Finally electrical recordings of neural response in close proximity are not contaminated by the excitation stimulus. Although electrical stimulation suffers from the above mentioned drawbacks it is still the most well established and reliable method for nerve stimulation in patients.

#### Infrared Stimulation

Infrared stimulation is based on an infrared laser inducing a local temperature gradient inside the neuron. It does not require any modification of the cells prior to stimulation. The low energy laser does not cause damage to the tissue and elicits an artefact free stimulation. The exact mechanisms that lead to neuronal discharge are not known. However studies have shown that this phenomenon is is most likely due to local photothermal processes. Thus the IR irradiation creates a temperature gradient confined to a small space which rapidly vanishes after irradiation ceases. The local temperature rise of up to 9°C is thought to cause conformational changes in molecules ultimately leading to neuronal firing. At high irradiation frequencies the heat becomes additive, causing the irradiated tissue to heat up gradually and ultimately damaging the cell.

#### Optogenetics

Optogenetics is the sensitisation of cells to light by the introduction of foreign genes, allowing temporal and spatial high resolution alteration of neural firing patterns. The genes can be expressed in genetic modification of animals or be introduced by vectors like viruses. Most light sensitizing genes used today were first discovered in unicellular organisms like algae or archaea. These genes can encode light sensitive ion channels or receptors producing various responses to optic stimulation.
For neuronal activation natural Channelrhodopsins (ChR) or engineered genetic variants thereof are commonly used. ChRs are light sensitive non-specific cation channels, which open when excited with blue light (480nm). In nerve cells ChR opening leads to sodium influx and membrane depolarisation. The light sensitive component is an all-trans-retinal which is also found in the human retina. Light induces a conformational change to 13-cis-retinal allowing cations to flow across the channel. Introduction of specific point mutations close to the retinal binding site can alter the kinetic properties and specificity of the channel. Linking ChR to other proteins allows for tools with diverse functionalities as in vivo monitoring of the introduced constructs.
Halorhodopsin (HR) are light gated chloride ion pumps used for light activated neuronal inhibition. Optical excitation by yellow light (570nm) in sensitized neurons leads to an import of chloride ions and hyperpolarisation. Like in ChR, the light sensitive molecule is also all-trans-retinal. Due to different stabilisation and thus wave length sensitivity differences of the retinal in HR and ChR, they can be used in the same cells and targeted separately. This allows for very close control of the activity in neural circuits.
For optical control of cell pathways the Opto-XR proteins were developed, where the X stands for the targeted signalling pathway. Opto-XRs consist of an animal-rhodopsin (bovine, rat etc.), with its intracellular domains exchanged for signalling sequences of the cell. This allows optic regulation of the cells signalling pathway. The signaling sequences can either be activated or deactivated by conformational changes induced by light falling on the rhodopsin. This allows for specific activation of certain receptor pathways like serotonin or adrenergic signalling.

### Optic stimulation in Neuro-Prosthetics

Electric stimulation has long been used for evoking nerve firing in neuronal prosthetics. However, spread of electrical current and generation of electric fields limit the spatial resolution that can be achieved. This limits the fidelity of the transmitted signal. In the case of auditory prostheses a maximum of around twenty electrodes is feasible, leaving the sound quality achieved far off the desired goal. A switch to optic based technology could achieve activation of smaller areas, increasing the amount of potentially perceived tones. Recent development in optic stimulation techniques promise ways to overcome those obstacles and improve prosthetic devices and the quality of live for patients.

#### Cochlear Implants

Infrared stimulation of the cochlea as well as the auditory nerve have been tested in various animal models such as rodents and cats. The optic variant shows remarkable precision concerning the area stimulated by the laser, which is approximately the same size as that activated by a medium loudness tone. It has also been shown that using low energy IR irradiation, constant stimulation can be achieved without gradual heating and damaging of the tissue. This enables the usage of the implant throughout the day without damaging the cochlear system. A major drawback of the IR stimulation is a much higher energy consumption compared to electrical stimulation.
To overcome the energy problem described, researchers have begun to test an optogenetic approach in rodents. They genetically engineered mice to express Channelrhodopsins in spinal ganglion neurons. Sensitisation of the nerve cells reduced the energy required to induce firing compared to IR irradiation by a factor of seven (IR: 15 μJ, Optogen.: 2 μJ, Electric: 0.2 μJ). Stimulation was thus possible using μLEDs instead of lasers. In spite of this progress, implementation of this technology in humans in the near future is questionable. This is mainly due to the possible dangers of viral introduction of genetic material into an organism. Up to now only very few gene therapies have been approved. A save but still effective way of specifically infecting the cochlear organs would have to be implemented and approved.
First patents have been registered describing potential optical cochlear implants for humans. These implants function similar to the traditional electrical implants. But instead of the electrodes they have VCSELs (vertical-cavity surface-emitting lasers) that are driven by the implant's input device. VCSELs are laser emitting diodes that can be fit into the small tubing of the implant. The lasers are directed at the organ of Corti and can be much closer spaced than electrodes, more than doubling the amount of implant output channels. Laser diodes are used for higher pitch signalling, while electrodes drive lower amplitude nerve cells.

#### Vestibular Prostheses

Vestibular Prostheses aim to restore imbalance issues arising from dysfunction of the vestibular system. Since the semicircular canals are interconnected, current spread is a major problem in electrical stimulus delivery. Current spread can lead to additional stimulation of unwanted semicircular canals, resulting in incorrect balance signals sent to the brain. The possibility of using IR irradiation has been investigated. Irradiation of the ampullae did not evoke action potentials. The reason for failing stimulation might lie in an insensitivity of the hair cells to IR irradiation. Nevertheless, optical stimulation of the vestibular nerve might be feasible. It is as of yet unclear if separate stimulation of the nerves from different ampullae is possible in this manner.

### References

* 1 2 Szobota, Stephanie; Isacoff, Ehud Y (2010). "Optical control of neuronal activity". Annual review of biophysics. 39: 329–348. {{cite journal}}: Cite has empty unknown parameter: |1= (help)
* 1 2 3 4 Richter, Claus-Peter; Matic, Agnella Izzo; Wells, Jonathon D; Jansen, E Duco; Walsh, Joseph T (2011). "Neural stimulation with optical radiation". Laser & photonics reviews. 5 (1): 68–80.
* 1 2 Wells, Jonathon D; Cayce, Jonathan M; Mahadevan-jansen, Anita; Konrad, Peter E; Jansen, E Duco (2011). "Infrared Nerve Stimulation: A Novel Therapeutic Laser Modality". Optical-Thermal Response of Laser-Irradiated Tissue (2 ed.). Dordrecht: Springer Netherlands. pp. 915–939.
* 1 2 Berthold, Peter; Tsunoda, Satoshi P; Ernst, Oliver P; Mages, Wolfgang; Gradmann, Dietrich; Hegemann, Peter (2008). "Channelrhodopsin-1 initiates phototaxis and photophobic responses in chlamydomonas by immediate light-induced depolarization". The Plant cell. 20 (6): 1665–1677.
* 1 2 Nagel, Georg; Szellas, Tanjef; Huhn, Wolfram; Kateriya, Suneel; Adeishvili, Nona; Berthold, Peter; Ollig, Doris; Hegemann, Peter; Bamberg, Ernst (2003). "Channelrhodopsin-2, a directly light-gated cation-selective membrane channel". Proceedings of the National Academy of Sciences. 100 (24): 13940–13945.
* ↑ Bamann, Christian; Kirsch, Taryn; Nagel, Georg; Bamberg, Ernst (2008). "Spectral characteristics of the photocycle of channelrhodopsin-2 and its implication for channel function". Journal of Molecular Biology. 375 (3): 686–694.
* ↑ Ernst, Oliver P; Sánchez Murcia, Pedro a; Daldrop, Peter; Tsunoda, Satoshi P; Kateriya, Suneel; Hegemann, Peter (2008). "Photoactivation of channelrhodopsin". The Journal of Biological Chemistry. 283 (3): 1637–1643.
* ↑ Gunaydin, Lisa; Yizhar, Ofer; Berndt, André; Sohal, Vikaas S; Deisseroth, Karl; Hegemann, Peter (2010). "Ultrafast optogenetic control". Nature neuroscience. 13 (3): 387–392.
* ↑ Lin, John Y; Lin, Michael Z; Steinbach, Paul; Tsien, Roger Y (2009). "Characterization of engineered channelrhodopsin variants with improved properties and kinetics". Biophysical journal. 96 (5): 1803–1814.
* ↑ Duschl, A; Lanyi, JK; Zimanyi, L (1990). "Properties and photochemistry of a halorhodopsin from the haloalkalophile, Natronobacterium pharaonis". Journal of Biological Chemistry. 265: 1261–1267.
* 1 2 Zhang, Feng; Wang, Li-Ping; Brauner, Martin; Liewald, Jana F; Kay, Kenneth; Watzke, Natalie; Wood, Phillip G; Bamberg, Ernst; Nagel, Georg; Gottschalk, Alexander; Deisseroth, Karl (2007). "Multimodal fast optical interrogation of neural circuitry". Nature. 446 (7136): 633–639.
* ↑ Han, Xue; Boyden, Edward S (2007). "Multiple-color optical activation, silencing, and desynchronization of neural activity, with single-spike temporal resolution". Plos one. 2 (3): e299.
* 1 2 Kim, Jong-myoung; Hwa, John; Garriga, Pere; Reeves, Philip J; Rajbhandary, Uttam L; Khorana, H Gobind (2005). "Light-Driven Activation of 2 -Adrenergic Receptor Signaling by a Chimeric Rhodopsin Containing the 2 -Adrenergic Receptor Cytoplasmic Loops". Biochemistry. 44 (7): 2284–2292.
* ↑ Airan, Raag D; Thompson, Kimberly R; Fenno, Lief E; Bernstein, Hannah; Deisseroth, Karl (2009). "Temporally precise in vivo control of intracellular signalling". Nature. 458 (7241): 1025–1029.
* ↑ Oh, Eugene; Maejima, Takashi; Liu, Chen; Deneris, Evan; Herlitze, Stefan (2010). "Substitution of 5-HT 1A Receptor Signaling by a Light-activated G Protein-coupled Receptor". The Journal of Biological Chemistry. 285 (40): 30825–30836.
* ↑ McGill, K C; Cummins, K L; Dorfman, L J; Berlizot, B B; Leutkemeyer, K; Nishimura, D G; Widrow, B (1982). "On the nature and elimination of stimulus artifact in nerve signals evoked and recorded using surface electrodes". IEEE transactions on bio-medical engineering. 29 (2): 129–137.
* ↑ Hernandez, VH; Gehrt, Anna; Reuter, Kirsten; Jing, Zhizi; Jeschke, Marcus; Schulz, Alejandro Mendoza; Hoch, Gerhard; Bartels, Matthias; Vogt, Gerhard; Garnham, Carolyn W.; Yawo, Hiromu; Fukazawa, Yugo; Augustine, George J.; Bamberg, Ernst; Kügler, Sebastian; Salditt, Tim; Hoz, Livia de; Strenzke, Nicola; Moser, Tobias (2014). "Optogenetic stimulation of the auditory pathway". The Journal of Clinical Investigation. 124 (3): 1114–1129.
* ↑ OPTICAL-STIMULATION COCHLEAR IMPLANT WITH ELECTRODE(S) AT THE APICAL END FOR ELECTRICAL STIMULATION OF APICAL SPIRAL GANGLION CELLS OF THE COCHLEA, Jan. 24, 2013 {{citation}}: Check date values in: |publication-date= (help); Unknown parameter |country-code= ignored (help); Unknown parameter |inventor-first= ignored (help); Unknown parameter |inventor-last= ignored (help); Unknown parameter |inventor2-first= ignored (help); Unknown parameter |inventor2-last= ignored (help); Unknown parameter |issue-date= ignored (help); Unknown parameter |patent-number= ignored (help)
* ↑ Harris, DM; Bierer, SM (2009). "Optical nerve stimulation for a vestibular prosthesis". Proceedings of SPIE. 5: 71800R.