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by Trevor Haynes

In the late 18th century a particularly resourceful experimenter, Giovanni Aldini, saw scientific opportunity in the increasingly prevalent public executions being performed across Europe at the time. Using the corpse of a recently deceased prisoner, Aldini electrically stimulated the prisoners exposed brain causing his eyes to open and his face to contort and twitch, thus putting his uncle’s theory of bioelectricity to practice for the first time in the human body. Grotesque, yes, but in addition to deeply disturbing his peers, Aldini opened the door for a technique that would become widely used in both science and medicine – deep brain stimulation (DBS) (Figure 1).

DBS has long been used as an invasive form of treatment prescribed for a range of brain diseases with varying degrees of success. It involves implanting electrodes into a patient’s brain to carry electrical current into the affected region, causing changes to surrounding brain cells’ (neurons’) activity. Because all neurons have evolved to be incredibly responsive to electrical stimuli, the electrical field generated by DBS affects the brain in a very broad manner. A single brain region is often composed of many different types of neurons, each performing a different function. Let’s say a problem with neuron type “A” is the root cause of a disease, and needs electrical stimulation to restore normal function. When an electrode is implanted into the brain region where type “A” neurons live and begins to stimulate the region, neurons type “B” and “C” who live in the same area are also affected. This has resulted in varying degrees of effectiveness with an array of potential side effects.

 

Figure 1: Basic DBS design. Patients are placed in a headframe while an MRI scan is taken to get a map of your brain and determine where the electrode(s) will be placed. They then receive local anesthesia on their skull, where surgeons make a small hole to slide the electrode and its lead to the target area. Patients are typically awake for this portion of the surgery so doctors can test the stimulation and ensure the electrode is in the correct location. With the electrode properly in place, patients are then put under general anesthesia so the pulse generator can be implanted in their chest. Pulse generators are remote controlled and programmable to customize stimulation frequencies. (Image from “Somatic Treatments for Mood Disorders” Liansby et al, Neuropscyhopharmacology 2011)
Figure 1: Basic DBS design. Patients are placed in a headframe while an MRI scan is taken to get a map of your brain and determine where the electrode(s) will be placed. They then receive local anesthesia on their skull, where surgeons make a small hole to slide the electrode and its lead to the target area. Patients are typically awake for this portion of the surgery so doctors can test the stimulation and ensure the electrode is in the correct location. With the electrode properly in place, patients are then put under general anesthesia so the pulse generator can be implanted in their chest. Pulse generators are remote controlled and programmable to customize stimulation frequencies. (Image from “Somatic Treatments for Mood Disorders” Liansby et al, Neuropscyhopharmacology 2011)

Although clinicians and researchers agree this treatment can be quite beneficial, we still lack a complete understanding of how it affects the brain, thus limiting our ability to improve it. Over the last decade, a new approach to controlling brain activity, called optogenetics, has emerged as a powerful research tool with exciting potential implications for DBS (Figure 2). Using insight gained from this new technique, clinicians may be able to refine their DBS technique to better suit patients and reduce the potential for unwanted side effects.

Controlling Brain Activity – Making a Neuron “Sneeze”

To appreciate the complementary nature of these techniques, it’s important to first understand how neurons operate. Neurons communicate with each other with chemical messages called “neurotransmitters”. These chemicals are packaged inside of the cell and can be sent to other parts of the brain through trillions of connections, resulting in huge networks of activity that produce our thoughts, emotions, and actions. In general, the release of these neurotransmitters requires a build of up of the positive charge inside the neuron until it reaches a threshold and “fires”. It’s sort of like the sensation of sneezing. You have this brief period of activity building up, followed by an intense release. Both DBS and optogenetics achieve this buildup of positive charge, though in very different ways. DBS gives the neurons direct electrical stimulation, whereas optogenetics uses light to cause a rapid influx of the positively charged ions through proteins that form pores in the surface of the neuron. It is this distinction that allows optogenetics to be used in a much more specific manner.

Figure 2: A comparison of DBS and optogenetics on a brain region with multiple types of neurons (Black/White) which perform independent actions in the brain. Neurons outlined in red represent activation by the stimulus. DBS (A) modulates the activity of neurons regardless of their function and genetic properties, while optogenetics (B) targets a specific subpopulation of neurons based on the presence of genetically encoded light-sensitive protein channels.
Figure 2: A comparison of DBS and optogenetics on a brain region with multiple types of neurons (Black/White) which perform independent actions in the brain. Neurons outlined in red represent activation by the stimulus. DBS (A) modulates the activity of neurons regardless of their function and genetic properties, while optogenetics (B) targets a specific subpopulation of neurons based on the presence of genetically encoded light-sensitive protein channels.

Optogenetics – An Overview

The invention of optogenetics has essentially given researchers “on/off” switches to brain regions of their choosing. Unlike DBS, which uses electricity to cause broad changes in the the activity of any neuron near the electrode, optogenetics uses light to target specific neurons, allowing us to hit type “A” neurons without affecting types “B” and “C.” Because neurons are not normally responsive to light, researchers must first make the neurons that they want to target light-sensitive. This is often accomplished in animal models by injecting a virus into the brain region of interest. This virus can be engineered to only infect specific neurons and to provide these specific neurons with “instructions” to coat themselves in proteins that the researchers can control with light. Bioengineers have invented a variety of these viruses which carry instructions for different types of light-sensitive proteins, some causing neurons to be more active, and some causing them to be less active.

Shining a Light in the Brain

Just as DBS uses an implantable electrode to stimulate a brain region, optogenetics requires the implantation of an optic fiber capable of delivering light to neurons deep in the brain. The standard approach for this utilizes implantable optic fibers that can emit light inside of the brain like a flashlight. These “flashlight fibers” are cheap, easy to implant, and can be kept in rodents for several weeks, giving researchers a versatile tool for performing optogenetic experiments. A light source such as a laser or an LED is coupled to exposed fiber and delivers light into the brain at different wavelengths and power, depending on the type of light-sensitive proteins coating the cells. These fibers are flat at their end, emitting light the shape of a cone just like your standard flashlight, illuminating neurons sitting below its tip. While they are not capable of illuminating large populations of neurons, they have enabled neuroscience researchers with a variety of scientific interests to better understand the various neuron types and study their roles in both normal function and disease.

Figure 3: Implantable “flashlight fiber” used to deliver light in to the brains of our mice. The white ceramic portion of the fiber will protrude from the animal’s skull where it can be coupled to a light source.
Figure 3: Implantable “flashlight fiber” used to deliver light in to the brains of our mice. The white ceramic portion of the fiber will protrude from the animal’s skull where it can be coupled to a light source.

Optogenetics and DBS: A Complementary Relationship

By selectively activating or deactivating specific groups of neurons, researchers can figure out what these neurons are doing and how they are interacting with other parts of the brain. Optogenetics essentially allows researchers to “map out” the connections in the brain that underlie behavior and identify specific neurons and connections that may be responsible for disease. With this information, DBS researchers are beginning to refine their techniques to create more effective therapies.

In one example, a research group investigating DBS as a potential therapy for addiction was unable to use DBS alone as a treatment for addiction in mice. But when the researchers paired DBS with a drug that targets overactive neurons identified in optogenetic studies, they successfully created a reduction in addictive behaviors not possible with either treatment alone. As DBS is not yet an FDA-approved therapy for addiction patients, research groups like this one are using insights gained from optogenetic studies to push DBS into that arena.

The Future of DBS

Although optogenetics still has obstacles to overcome before it can be considered as a viable therapy for patients, its power as a research tool in animal models and guiding light to DBS protocols is clear. Current electrical DBS targets inspire optogenetic studies into a brain region, and insights gained from the optogenetic studies can be used to refine the DBS’s effectiveness. Until recently, the ability of optogenetic studies to refine DBS therapy has been limited by the use of flashlight fibers, which produce smaller areas of activation. The DBS electrode creates an electrical field within the brain, exerting its effects on a large population of neurons while the flashlight fiber, by comparison, is only able to exert its effects on a smaller population of neurons below its tip. With such a small area of activation, it can be difficult for researchers to make meaningful inferences out of their observations. In 2016, a new type of fiber was developed capable of matching the area of activation created by a DBS electrode, while minimizing collateral damage to brain. This new fiber, the “Lambda B”, will enable researchers to parse out the roles of different neuron types in a DBS region without sacrificing the large area of activation necessary to emulate the therapy.

Figure 4: The Lambda B fiber next to the flashlight fiber shown above. The Lambda B fiber is capable of emitting light along its length, looking like a glow stick when illuminated. Its flexible streamlined shape allows for it to be implanted deep into the animals brain without causing significant damage when compared to the rigid flashlight fiber. Perhaps the Lambda B’s most powerful advantage is the ability to selectively illuminate segments along its length by adjusting the angle in which light enters the top, allowing researchers to independently illuminate different groups of neurons in a single animal.
Figure 4: The Lambda B fiber next to the flashlight fiber shown above. The Lambda B fiber is capable of emitting light along its length, looking like a glow stick when illuminated. Its flexible streamlined shape allows for it to be implanted deep into the animals brain without causing significant damage when compared to the rigid flashlight fiber. Perhaps the Lambda B’s most powerful advantage is the ability to selectively illuminate segments along its length by adjusting the angle in which light enters the top, allowing researchers to independently illuminate different groups of neurons in a single animal.

Capitalizing on the neuron type specificity offered by optogenetics and the large activation area possible with fibers like the Lambda B, researchers will be able to determine which neurons produce the therapeutic effects of DBS, and which might be responsible for undesirable side effects. This information may lead to more drug-paired DBS therapies, as in the addiction study mentioned earlier, or completely new strategies for refining DBS. Perhaps more excitingly, we may even see DBS being prescribed to treat a wider range of brain diseases, such as OCD and depression (both which currently being investigated).

Figure 3. Illustrations of activation areas of DBS electrode (A), standard optogenetic fiber (B), and the Lambda B (C). To effectively emulate DBS stimulation using optogenetics, the optic fiber must be able to activate a large population of neurons like the electrode used in DBS. Using this tool will allow researchers using optogenetics to determine, for example, that stimulation of black neurons alleviates a disease symptom, while stimulating white neurons produces nausea or dizziness. Using this information, clinicians may design a DBS protocol that only exerts its effects on the black neurons with the use of a secondary therapy.
Figure 5: Illustrations of activation areas of DBS electrode (A), standard optogenetic fiber (B), and the Lambda B (C). To effectively emulate DBS stimulation using optogenetics, the optic fiber must be able to activate a large population of neurons like the electrode used in DBS. Using this tool will allow researchers using optogenetics to determine, for example, that stimulation of black neurons alleviates a disease symptom, while stimulating white neurons produces nausea or dizziness. Using this information, clinicians may design a DBS protocol that only exerts its effects on the black neurons with the use of a secondary therapy.

At the end of the day, the underlying goal of researchers and physicians alike is to better understand the systems responsible for our experiences and apply therapies to alleviate the suffering that occurs when these systems break down. Exploiting the complementary nature of research and medical techniques such as optogenetics and DBS allows the two communities to build upon each other in a very powerful way, and improve the quality of life of many people who suffer from brain disease. With the rate of scientific discovery accelerating, it is safe to say exciting times lay ahead!

Trevor Haynes is a Neurobiology Research Technician at Harvard Medical School. With a group of HMS researchers and in collaboration with the Italian Institute of Technology, he directly took part in the development of the Lambda B fiber and other optogenetic approaches to studying the brain.

Check out more SITN articles describing other applications of optogenetics:

Total Recall: Using Light to Create and Erase Memories

Mind Control: Mapping Motivation with Light

Optogenetics: Can Chronic Pain Be Treated with Light

 

The Lambda B fiber was developed by Optogenix, a collaboration between researchers at Harvard Medical School and the Italian Institute of Technology. For more information regarding this technology please visit their website.

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