Brain implant

From Wikipedia, the free encyclopedia

A laboratory rat with a brain implant used to record neuronal activity

 

Brain implants, often referred to as neural implants, are technological devices that connect directly to a biological subject's brain – usually placed on the surface of the brain, or attached to the brain's cortex. A common purpose of modern brain implants and the focus of much current research is establishing a biomedical prosthesis circumventing areas in the brain that have become dysfunctional after a stroke or other head injuries. This includes sensory substitution, e.g., in vision. Other brain implants are used in animal experiments simply to record brain activity for scientific reasons. Some brain implants involve creating interfaces between neural systems and computer chips. This work is part of a wider research field called brain-computer interfaces. (Brain-computer interface research also includes technology such as EEG arrays that allow interface between mind and machine but do not require direct implantation of a device.) 

Neural implants such as deep brain stimulation and Vagus nerve stimulation are increasingly becoming routine for patients with Parkinson's disease and clinical depression, respectively.

Purpose

Brain implants electrically stimulate, block or record (or both record and stimulate simultaneously) signals from single neurons or groups of neurons (biological neural networks) in the brain. The blocking technique is called intra-abdominal vagal blocking. This can only be done where the functional associations of these neurons are approximately known. Because of the complexity of neural processing and the lack of access to action potential related signals using neuroimaging techniques, the application of brain implants has been seriously limited until recent advances in neurophysiology and computer processing power.

Research and applications

Research in sensory substitution has made significant progress since 1970. Especially in vision, due to the knowledge of the working of the visual system, eye implants (often involving some brain implants or monitoring) have been applied with demonstrated success. For hearing, cochlear implants are used to stimulate the auditory nerve directly. The vestibulocochlear nerve is part of the peripheral nervous system, but the interface is similar to that of true brain implants. 

Multiple projects have demonstrated success at recording from the brains of animals for long periods of time. As early as 1976, researchers at the NIH led by Edward Schmidt made action potential recordings of signals from rhesus monkey motor cortexes using immovable "hatpin" electrodes, including recording from single neurons for over 30 days, and consistent recordings for greater than three years from the best electrodes. 

The "hatpin" electrodes were made of pure iridium and insulated with Parylene-c, materials that are currently used in the Cyberkinetics implementation of the Utah array. These same electrodes, or derivations thereof using the same biocompatible electrode materials, are currently used in visual prosthetics laboratories, laboratories studying the neural basis of learning, and motor prosthetics approaches other than the Cyberkinetics probes.

Schematic of the "Utah" Electrode Array

Other laboratory groups produce their own implants to provide unique capabilities not available from the commercial products.

Breakthroughs include studies of the process of functional brain re-wiring throughout the learning of a sensory discrimination, control of physical devices by rat brains, monkeys over robotic arms, remote control of mechanical devices by monkeys and humans, remote control over the movements of roaches, electronic-based neuron transistors for leeches, the first reported use of the Utah Array in a human for bidirectional signalling. Currently a number of groups are conducting preliminary motor prosthetic implants in humans. These studies are presently limited to several months by the longevity of the implants. The array now forms the sensor component of the Braingate. 

Much research is also being done on the surface chemistry of neural implants in effort to design products which minimize all negative effects that an active implant can have on the brain, and that the body can have on the function of the implant. 

Another type of neural implant that is being experimented on is Prosthetic Neuronal Memory Silicon Chips, which imitate the signal processing done by functioning neurons that allows peoples' brains to create long-term memories. 

In 2016, scientists at the University of Illinois at Urbana–Champaign announced development of tiny brain sensors for use postoperative monitoring, which melt away when they are no longer needed.

Military

DARPA has announced its interest in developing "cyborg insects" to transmit data from sensors implanted into the insect during the pupal stage. The insect's motion would be controlled from a Micro-Electro-Mechanical System (MEMS) and could conceivably survey an environment or detect explosives and gas. Similarly, DARPA is developing a neural implant to remotely control the movement of sharks. The shark's unique senses would then be exploited to provide data feedback in relation to enemy ship movement or underwater explosives.

In 2006, researchers at Cornell University invented a new surgical procedure to implant artificial structures into insects during their metamorphic development. The first insect cyborgs, moths with integrated electronics in their thorax, were demonstrated by the same researchers. The initial success of the techniques has resulted in increased research and the creation of a program called Hybrid-Insect-MEMS, HI-MEMS. Its goal, according to DARPA's Microsystems Technology Office, is to develop "tightly coupled machine-insect interfaces by placing micro-mechanical systems inside the insects during the early stages of metamorphosis".

The use of neural implants has recently been attempted, with success, on cockroaches. Surgically applied electrodes were put on the insect, which were remotely controlled by a human. The results, although sometimes different, basically showed that the cockroach could be controlled by the impulses it received through the electrodes. DARPA is now funding this research because of its obvious beneficial applications to the military and other areas.

In 2009 at the Institute of Electrical and Electronics Engineers (IEEE) Micro-electronic mechanical systems (MEMS) conference in Italy, researchers demonstrated the first "wireless" flying-beetle cyborg. Engineers at the University of California at Berkeley have pioneered the design of a "remote controlled beetle", funded by the DARPA HI-MEMS Program. Filmed evidence of this can be viewed here. This was followed later that year by the demonstration of wireless control of a "lift-assisted" moth-cyborg.

Eventually researchers plan to develop HI-MEMS for dragonflies, bees, rats and pigeons. For the HI-MEMS cybernetic bug to be considered a success, it must fly 100 metres (330 ft) from a starting point, guided via computer into a controlled landing within 5 metres (16 ft) of a specific end point. Once landed, the cybernetic bug must remain in place.

In 2015 it was reported that scientists from the Perception and Recognition Neuro-technologies Laboratory at the Southern Federal University in Rostov-on-Don suggested using rats with microchips planted in their brains to detect explosive devices.

In 2016 it was reported that American engineers are developing a system that would transform locusts into "remote controlled explosive detectors" with electrodes in their brains beaming information about dangerous substances back to their operators.

Rehabilitation

Neurostimulators have been in use since 1997 to ease the symptoms of such diseases as epilepsy, Parkinson's Disease, dystonia and recently depression. 

Current brain implants are made from a variety of materials such as tungsten, silicon, platinum-iridium, or even stainless steel. Future brain implants may make use of more exotic materials such as nanoscale carbon fibers (nanotubes), and polycarbonate urethane.

Historical research

In 1870, Eduard Hitzig and Gustav Fritsch demonstrated that electrical stimulation of the brains of dogs could produce movements. Robert Bartholow showed the same to be true for humans in 1874. By the start of the 20th century, Fedor Krause began to systematically map human brain areas, using patients that had undergone brain surgery. 

Prominent research was conducted in the 1950s. Robert G. Heath experimented with aggressive mental patients, aiming to influence his subjects' moods through electrical stimulation.

Yale University physiologist Jose Delgado demonstrated limited control of animal and human subjects' behaviours using electronic stimulation. He invented the stimoceiver or transdermal stimulator, a device implanted in the brain to transmit electrical impulses that modify basic behaviours such as aggression or sensations of pleasure. 

Delgado was later to write a popular book on mind control, called Physical Control of the Mind, where he stated: "the feasibility of remote control of activities in several species of animals has been demonstrated [...] The ultimate objective of this research is to provide an understanding of the mechanisms involved in the directional control of animals and to provide practical systems suitable for human application." 

In the 1950s, the CIA also funded research into mind control techniques, through programs such as MKULTRA. Perhaps because he received funding for some research through the US Office of Naval Research, it has been suggested (but not proven) that Delgado also received backing through the CIA. He denied this claim in a 2005 article in Scientific American describing it only as a speculation by conspiracy-theorists. He stated that his research was only progressively scientifically motivated to understand how the brain works.

Concerns and ethical considerations

Ethical questions raised include who are good candidates to receive neural implants and what are good and bad uses of neural implants. Whilst deep brain stimulation is increasingly becoming routine for patients with Parkinson's disease, there may be some behavioural side effects. Reports in the literature describe the possibility of apathy, hallucinations, compulsive gambling, hypersexuality, cognitive dysfunction, and depression. However, these may be temporary and related to correct placement and calibration of the stimulator and so are potentially reversible.

Some transhumanists, such as Raymond Kurzweil and Kevin Warwick, see brain implants as part of a next step for humans in progress and evolution, whereas others, especially bioconservatives, view them as unnatural, with humankind losing essential human qualities. It raises controversy similar to other forms of human enhancement. For instance, it is argued that implants would technically change people into cybernetic organisms (cyborgs). It's also expected that all research will comply to the Declaration of Helsinki. Yet further, the usual legal duties apply such as information to the person wearing implants and that the implants are voluntary, with (very) few exceptions. 

Other concerns involve vulnerabilities of neural implants to cybercrime or intrusive surveillance as neural implants could be hacked, misused or misdesigned.

Sadja states that "one's private thoughts are important to protect" and doesn't consider it a good idea to just charge the government or any company with protecting them. Walter Glannon, a neuroethicist of the University of Calgary notes that "there is a risk of the microchips being hacked by third parties" and that "this could interfere with the user's intention to perform actions, violate privacy by extracting information from the chip".

In fiction and philosophy

Brain implants are now part of modern culture but there were early philosophical references of relevance as far back as René Descartes. 

In his 1641 Meditations, Descartes argued that it would be impossible to tell if all one's apparently real experiences were in fact being produced by an evil demon intent on deception. A modern twist on Descartes' argument is provided by the "brain in a vat" thought experiment, which imagines a brain, sustained apart from its body in a vat of nutrients, and hooked up to a computer which is capable of stimulating it in such a way as to produce the illusion that everything is normal.

Popular science fiction discussing brain implants and mind control became widespread in the 20th century, often with a dystopian outlook. Literature in the 1970s delved into the topic, including The Terminal Man by Michael Crichton, where a man suffering from brain damage receives an experimental surgical brain implant designed to prevent seizures, which he abuses by triggering for pleasure. Another example is Larry Niven's science fiction writing of wire-heads in his "Known Space" stories. 

Fear that the technology will be misused by the government and military is an early theme. In the 1981 BBC serial The Nightmare Man the pilot of a high-tech mini submarine is linked to his craft via a brain implant but becomes a savage killer after ripping out the implant. 

Perhaps the most influential novel exploring the world of brain implants was William Gibson's 1984 novel Neuromancer. This was the first novel in a genre that came to be known as "cyberpunk". It follows a computer hacker through a world where mercenaries are augmented with brain implants to enhance strength, vision, memory, etc. Gibson coins the term "matrix" and introduces the concept of "jacking in" with head electrodes or direct implants. He also explores possible entertainment applications of brain implants such as the "simstim" (simulated stimulation) which is a device used to record and playback experiences.

Another example is "The Alliance ", in which a society is controlled by implants. Gibson's work led to an explosion in popular culture references to brain implants. Its influences are felt, for example, in the 1989 roleplaying game Shadowrun, which borrowed his term "datajack" to describe a brain-computer interface. The implants in Gibson's novels and short stories formed the template for the 1995 film Johnny Mnemonic and later, The Matrix Trilogy. 

Pulp fiction with implants or brain implants include the novel series Typers, film Spider-Man 2, the TV series Earth: Final Conflict, and numerous computer/video games.

• The Gap Cycle (The Gap into): In Stephen R. Donaldson's series of novels, the use (and misuse) of "zone implant" technology is key to several plotlines.
• Ghost in the Shell anime and manga franchise: Cyberbrain neural augmentation technology is the focus. Implants of powerful computers provide vastly increased memory capacity, total recall, as well as the ability to view his or her own memories on an external viewing device. Users can also initiate a telepathic conversation with other cyberbrain users, the downsides being cyberbrain hacking, malicious memory alteration, and the deliberate distortion of subjective reality and experience.
• In Larry Niven and Jerry Pournelle's Oath of Fealty (1981) an arcology with high surveillance and feudal-like society is built by a private company due to riots around Los Angeles. Its systems are run by MILLIE, an advanced computer system, with some high-level executives being able to communicate directly with it and given omniscience of the arcology's workings via expensive implants in their brains.

Film

• Brainstorm (1983): The military tries to take control over a new technology that can record and transfer thoughts, feelings, and sensations.
• RoboCop (1987) Science fiction action film. Police officer Alex Murphy is murdered and revived as a superhuman cyborg law enforcer.
• Johnny Mnemonic (1995): The main character acts as a "mnemonic courier" by way of a storage implant in his brain, allowing him to carry sensitive information undetected between parties.
• The Manchurian Candidate (2004): For a means of mind control, the presidential hopeful Raymond Shaw unknowingly has a chip implanted in his head by Manchurian Global, a fictional geopolitical organization aimed at making parts of the government sleeper cells, or puppets for their monetary advancement.
• Hardwired (2009): A corporation attempting to bring marketing to the next level implants a chip into main character's brain.
• Terminator Salvation (2009): A character named Marcus Wright discovers he is a Cyborg and must choose to fight for humans or an evil Artificial intelligence.

Television

• The Happiness Cage (1972) A German scientist works on a way of quelling overly aggressive soldiers by developing implants that directly stimulate the pleasure centers of the brain. Also known as The Mind Snatchers.
• Six Million Dollar Man (1974 to 1978) Steve Austin suffers an accident and is rebuilt as a cyborg.
• The Bionic Woman (1976 to 1978) Jaime Sommers suffers an accident and is rebuilt as a cyborg.
• Blake's 7: Olag Gan, a character, has a brain implant which is supposed to prevent future aggression after being convicted of killing an officer from the oppressive Federation.
• Dark Angel: The notorious Red Series use neuro-implants pushed into their brain stem at the base of their skull to amp them up and hyper-adrenalize them and make them almost unstoppable. Unfortunately the effects of the implant burn out their system after six months to a year and kill them.
• The X-Files (episode:Duane Barry, relevant to the overreaching mytharc of the series.): FBI Agent Dana Scully discovers an implant set under the skin at the back of her neck which can read her every thought and change memory through electrical signals that alter the brain chemistry.
• Star Trek franchise: Members of the Borg collective are equipped with brain implants which connect them to the Borg collective consciousness.
• Stargate SG-1 franchise: Advanced replicators, the Asuran interface with humans by inserting their hand into the brain of humans.
• Fringe: The Observers use a needle like, self-guided implant which allows them to read the minds of others at the expense of emotion. The implant also allows for short range teleportation and increases intelligence.
• Person of Interest, Season 4. Episode 81 or 13. Title "M.I.A" "One of many innocent people who Samaritan operatives are experimenting on with neural implants."
• In the Outer Limits (1995 TV series), the episode named Straight and Narrow (The Outer Limits). Students are forced to have brain implants and are controlled by them.
• In the Outer Limits (1995 TV series), the episode named The Message (The Outer Limits). A character named Jennifer Winter receives a brain implant to hear.
• In the Outer Limits (1995 TV series), the episode named "Living Hell", season 1 episode 9. A character named Ben Kohler receives a brain implant to save his life.
• In the Outer Limits (1995 TV series), the episode named Judgment Day (The Outer Limits), A character who is judged a criminal has a chip implanted on the medulla oblongata of the lower brainstem . The forcibly implanted chip induces overwhelming pain and disorientation by a remote control within range.
• In the Outer Limits (1995 TV series), the episode named "Awakening", season three, episode 10, a neurologically impaired woman receives a brain implant to help her become more like a typical human.
• Black Mirror, a British science fiction television anthology series, has several episodes in which characters have implants on their head or in their brain or eyes, providing video recording and playback, augmented reality, and communication.
• Earth: Final Conflict, in season 1, episode 12, named "Sandoval's Run", the character named Sandoval experiences the breakdown of his brain implant.
• Earth: Final Conflict, in season 4, episode 12, named "The Summit", the character named Liam is implanted with a neural surveillance device.

Video games

• In the video games PlanetSide and Chrome, players can use implants to improve their aim, run faster, and see better, along with other enhancements.
• The Deus Ex video game series addresses the nature and impact of human enhancement with regard to a wide variety of prosthesis and brain implants. Deus Ex: Human Revolution, set in 2027, details the impact on society of human augmentation and the controversy it could generate. Several characters in the game have implanted neurochips to aid their professions (or their whims). Examples are of a helicopter pilot with implanted chips to better pilot her aircraft and analyse flight paths, velocity and spatial awareness, as well as a hacker with a brain-computer interface that allows direct access to computer networks and also to act as a 'human proxy' to allow an individual in a remote location to control his actions.

The game raises the question of the downsides of this kind of augmentation as those who cannot afford the enhancements (or object to getting them) rapidly find themselves at a serious disadvantage against people with artificial enhancement of their abilities. The spectre of being forced to have mechanical or electronic enhancements just to get a job is explored as well. The storyline addresses the effect of implant rejection by use of the fictional drug 'Neuropozyne' which breaks down glial tissue and is also fiercely addictive, leaving people who have augmentations little choice but to continue buying the drug from biotech corporations who control the price of it. Without the drug, augmented people experience rejection of implants, crippling pain and possible death.

Neurotechnology

From Wikipedia, the free encyclopedia

Neurotechnology is any technology that has a fundamental influence on how people understand the brain and various aspects of consciousness, thought, and higher order activities in the brain. It also includes technologies that are designed to improve and repair brain function and allow researchers and clinicians to visualize the brain.

Background

The field of neurotechnology has been around for nearly half a century but has only reached maturity in the last twenty years. The advent of brain imaging revolutionized the field, allowing researchers to directly monitor the brain's activities during experiments. Neurotechnology has made significant impact on society, though its presence is so commonplace that many do not realize its ubiquity. From pharmaceutical drugs to brain scanning, neurotechnology affects nearly all industrialized people either directly or indirectly, be it from drugs for depression, sleep, ADD, or anti-neurotics to cancer scanning, stroke rehabilitation, and much more. 

As the field's depth increases it will potentially allow society to control and harness more of what the brain does and how it influences lifestyles and personalities. Commonplace technologies already attempt to do this; games like BrainAge, and programs like Fast ForWord that aim to improve brain function, are neurotechnologies. 

Currently, modern science can image nearly all aspects of the brain as well as control a degree of the function of the brain. It can help control depression, over-activation, sleep deprivation, and many other conditions. Therapeutically it can help improve stroke victims' motor coordination, improve brain function, reduce epileptic episodes, improve patients with degenerative motor diseases (Parkinson's disease, Huntington's disease, ALS), and can even help alleviate phantom pain perception. Advances in the field promise many new enhancements and rehabilitation methods for patients suffering from neurological problems. The neurotechnology revolution has given rise to the Decade of the Mind initiative, which was started in 2007. It also offers the possibility of revealing the mechanisms by which mind and consciousness emerge from the brain.

Current technologies

Live Imaging

Magnetoencephalography is a functional neuroimaging technique for mapping brain activity by recording magnetic fields produced by electrical currents occurring naturally in the brain, using very sensitive magnetometers. Arrays of SQUIDs (superconducting quantum interference devices) are the most common magnetometer. Applications of MEG include basic research into perceptual and cognitive brain processes, localizing regions affected by pathology before surgical removal, determining the function of various parts of the brain, and neurofeedback. This can be applied in a clinical setting to find locations of abnormalities as well as in an experimental setting to simply measure brain activity.

Magnetic resonance imaging (MRI) is used for scanning the brain for topological and landmark structure in the brain, but can also be used for imaging activation in the brain. While detail about how MRI works is reserved for the actual MRI article, the uses of MRI are far reaching in the study of neuroscience. It is a cornerstone technology in studying the mind, especially with the advent of functional MRI (fMRI). Functional MRI measures the oxygen levels in the brain upon activation (higher oxygen content = neural activation) and allows researchers to understand what loci are responsible for activation under a given stimulus. This technology is a large improvement to single cell or loci activation by means of exposing the brain and contact stimulation. Functional MRI allows researchers to draw associative relationships between different loci and regions of the brain and provides a large amount of knowledge in establishing new landmarks and loci in the brain.

Computed tomography (CT) is another technology used for scanning the brain. It has been used since the 1970s and is another tool used by neuroscientists to track brain structure and activation. While many of the functions of CT scans are now done using MRI, CT can still be used as the mode by which brain activation and brain injury are detected. Using an X-ray, researchers can detect radioactive markers in the brain that indicate brain activation as a tool to establish relationships in the brain as well as detect many injuries/diseases that can cause lasting damage to the brain such as aneurysms, degeneration, and cancer. 

Positron emission tomography (PET) is another imaging technology that aids researchers. Instead of using magnetic resonance or X-rays, PET scans rely on positron emitting markers that are bound to a biologically relevant marker such as glucose. The more activation in the brain the more that region requires nutrients, so higher activation appears more brightly on an image of the brain. PET scans are becoming more frequently used by researchers because PET scans are activated due to metabolism whereas MRI is activated on a more physiological basis (sugar activation versus oxygen activation).

Transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is essentially direct magnetic stimulation to the brain. Because electric currents and magnetic fields are intrinsically related, by stimulating the brain with magnetic pulses it is possible to interfere with specific loci in the brain to produce a predictable effect. This field of study is currently receiving a large amount of attention due to the potential benefits that could come out of better understanding this technology. Transcranial magnetic movement of particles in the brain shows promise for drug targeting and delivery as studies have demonstrated this to be noninvasive on brain physiology.

Transcranial direct current stimulation

Transcranial direct current stimulation (tDCS) is a form of neurostimulation which uses constant, low current delivered via electrodes placed on the scalp. The mechanisms underlying tDCS effects are still incompletely understood, but recent advances in neurotechnology allowing for in vivo assessment of brain electric activity during tDCS promise to advance understanding of these mechanisms. Research into using tDCS on healthy adults have demonstrated that tDCS can increase cognitive performance on a variety of tasks, depending on the area of the brain being stimulated. tDCS has been used to enhance language and mathematical ability (though one form of tDCS was also found to inhibit math learning), attention span, problem solving, memory, and coordination.

Cranial surface measurements

Electroencephalography (EEG) is a method of measuring brainwave activity non-invasively. A number of electrodes are placed around the head and scalp and electrical signals are measured. Typically EEGs are used when dealing with sleep, as there are characteristic wave patterns associated with different stages of sleep. Clinically EEGs are used to study epilepsy as well as stroke and tumor presence in the brain. EEGs are a different method to understand the electrical signaling in the brain during activation. 

Magnetoencephalography (MEG) is another method of measuring activity in the brain by measuring the magnetic fields that arise from electrical currents in the brain. The benefit to using MEG instead of EEG is that these fields are highly localized and give rise to better understanding of how specific loci react to stimulation or if these regions over-activate (as in epileptic seizures).

Implant technologies

Neurodevices are any devices used to monitor or regulate brain activity. Currently there are a few available for clinical use as a treatment for Parkinson's disease. The most common neurodevices are deep brain stimulators (DBS) that are used to give electrical stimulation to areas stricken by inactivity. Parkinson's disease is known to be caused by an inactivation of the basal ganglia (nuclei) and recently DBS has become the more preferred form of treatment for Parkinson's disease, although current research questions the efficiency of DBS for movement disorders.

Neuromodulation is a relatively new field that combines the use of neurodevices and neurochemistry. The basis of this field is that the brain can be regulated using a number of different factors (metabolic, electrical stimulation, physiological) and that all these can be modulated by devices implanted in the neural network. While currently this field is still in the researcher phase, it represents a new type of technological integration in the field of neurotechnology. The brain is a very sensitive organ, so in addition to researching the amazing things that neuromodulation and implanted neural devices can produce, it is important to research ways to create devices that elicit as few negative responses from the body as possible. This can be done by modifying the material surface chemistry of neural implants.

Cell therapy

Researchers have begun looking at uses for stem cells in the brain, which recently have been found in a few loci. A large number of studies are being done to determine if this form of therapy could be used in a large scale. Experiments have successfully used stem cells in the brains of children who suffered from injuries in gestation and elderly people with degenerative diseases in order to induce the brain to produce new cells and to make more connections between neurons.

Pharmaceuticals

Pharmaceuticals play a vital role in maintaining stable brain chemistry, and are the most commonly used neurotechnology by the general public and medicine. Drugs like sertraline, methylphenidate, and zolpidem act as chemical modulators in the brain, and they allow for normal activity in many people whose brains cannot act normally under physiological conditions. While pharmaceuticals are usually not mentioned and have their own field, the role of pharmaceuticals is perhaps the most far-reaching and commonplace in modern society (the focus on this article will largely ignore neuropharmaceuticals, for more information, see neuropsychopharmacology). Movement of magnetic particles to targeted brain regions for drug delivery is an emerging field of study and causes no detectable circuit damage.

Low field magnetic stimulation

Stimulation with low-intensity magnetic fields is currently under study for depression at Harvard Medical School, and has previously been explored by Bell. It has FDA approval for treatment of depression. It is also being researched for other applications such as autism. One issue is that no 2 brains are alike and stimulation can cause either polarization or depolarization. (et al.), Marino (et al.), and others.

How these help study the brain

Magnetic resonance imaging is a vital tool in neurological research in showing activation in the brain as well as providing a comprehensive image of the brain being studied. While MRIs are used clinically for showing brain size, it still has relevance in the study of brains because it can be used to determine extent of injuries or deformation. These can have a significant effect on personality, sense perception, memory, higher order thinking, movement, and spatial understanding. However, current research tends to focus more so on fMRI or real-time functional MRI (rtfMRI). These two methods allow the scientist or the participant, respectively, to view activation in the brain. This is incredibly vital in understanding how a person thinks and how their brain reacts to a person's environment, as well as understanding how the brain works under various stressors or dysfunctions. Real-time functional MRI is a revolutionary tool available to neurologists and neuroscientists because patients can see how their brain reacts to stressors and can perceive visual feedback. CT scans are very similar to MRI in their academic use because they can be used to image the brain upon injury, but they are more limited in perceptual feedback. CTs are generally used in clinical studies far more than in academic studies, and are found far more often in a hospital than a research facility. PET scans are also finding more relevance in academia because they can be used to observe metabolic uptake of neurons, giving researchers a wider perspective about neural activity in the brain for a given condition. Combinations of these methods can provide researchers with knowledge of both physiological and metabolic behaviors of loci in the brain and can be used to explain activation and deactivation of parts of the brain under specific conditions.

Transcranial magnetic stimulation is a relatively new method of studying how the brain functions and is used in many research labs focused on behavioral disorders and hallucinations. What makes TMS research so interesting in the neuroscience community is that it can target specific regions of the brain and shut them down or activate temporarily; thereby changing the way the brain behaves. Personality disorders can stem from a variety of external factors, but when the disorder stems from the circuitry of the brain TMS can be used to deactivate the circuitry. This can give rise to a number of responses, ranging from “normality” to something more unexpected, but current research is based on the theory that use of TMS could radically change treatment and perhaps act as a cure for personality disorders and hallucinations. Currently, repetitive transcranial magnetic stimulation (rTMS) is being researched to see if this deactivation effect can be made more permanent in patients suffering from these disorders. Some techniques combine TMS and another scanning method such as EEG to get additional information about brain activity such as cortical response.

Both EEG and MEG are currently being used to study the brain's activity under different conditions. Each uses similar principles but allows researchers to examine individual regions of the brain, allowing isolation and potentially specific classification of active regions. As mentioned above, EEG is very useful in analysis of immobile patients, typically during the sleep cycle. While there are other types of research that utilize EEG, EEG has been fundamental in understanding the resting brain during sleep. There are other potential uses for EEG and MEG such as charting rehabilitation and improvement after trauma as well as testing neural conductivity in specific regions of epileptics or patients with personality disorders. 

Neuromodulation can involve numerous technologies combined or used independently to achieve a desired effect in the brain. Gene and cell therapy are becoming more prevalent in research and clinical trials and these technologies could help stunt or even reverse disease progression in the central nervous system. Deep brain stimulation is currently used in many patients with movement disorders and is used to improve the quality of life in patients. While deep brain stimulation is a method to study how the brain functions per se, it provides both surgeons and neurologists important information about how the brain works when certain small regions of the basal ganglia (nuclei) are stimulated by electrical currents.

Future technologies

The future of neurotechnologies lies in how they are fundamentally applied, and not so much on what new versions will be developed. Current technologies give a large amount of insight into the mind and how the brain functions, but basic research is still needed to demonstrate the more applied functions of these technologies. Currently, rtfMRI is being researched as a method for pain therapy. deCharms et al. have shown that there is a significant improvement in the way people perceive pain if they are made aware of how their brain is functioning while in pain. By providing direct and understandable feedback, researchers can help patients with chronic pain decrease their symptoms. This new type of bio/mechanical-feedback is a new development in pain therapy. Functional MRI is also being considered for a number of more applicable uses outside of the clinic. Research has been done on testing the efficiency of mapping the brain in the case when someone lies as a new way to detect lying. Along the same vein, EEG has been considered for use in lie detection as well. TMS is being used in a variety of potential therapies for patients with personality disorders, epilepsy, PTSD, migraine, and other brain-firing disorders, but has been found to have varying clinical success for each condition. The end result of such research would be to develop a method to alter the brain's perception and firing and train patients' brains to rewire permanently under inhibiting conditions (for more information see rTMS). In addition, PET scans have been found to be 93% accurate in detecting Alzheimer's disease nearly 3 years before conventional diagnosis, indicating that PET scanning is becoming more useful in both the laboratory and the clinic.

Stem cell technologies are always salient both in the minds of the general public and scientists because of their large potential. Recent advances in stem cell research have allowed researchers to ethically pursue studies in nearly every facet of the body, which includes the brain. Research has shown that while most of the brain does not regenerate and is typically a very difficult environment to foster regeneration, there are portions of the brain with regenerative capabilities (specifically the hippocampus and the olfactory bulbs). Much of the research in central nervous system regeneration is how to overcome this poor regenerative quality of the brain. It is important to note that there are therapies that improve cognition and increase the amount of neural pathways, but this does not mean that there is a proliferation of neural cells in the brain. Rather, it is called a plastic rewiring of the brain (plastic because it indicates malleability) and is considered a vital part of growth. Nevertheless, many problems in patients stem from death of neurons in the brain, and researchers in the field are striving to produce technologies that enable regeneration in patients with stroke, Parkinson's diseases, severe trauma, and Alzheimer's disease, as well as many others. While still in fledgling stages of development, researchers have recently begun making very interesting progress in attempting to treat these diseases. Researchers have recently successfully produced dopaminergic neurons for transplant in patients with Parkinson's diseases with the hopes that they will be able to move again with a more steady supply of dopamine. Many researchers are building scaffolds that could be transplanted into a patient with spinal cord trauma to present an environment that promotes growth of axons (portions of the cell attributed with transmission of electrical signals) so that patients unable to move or feel might be able to do so again. The potentials are wide-ranging, but it is important to note that many of these therapies are still in the laboratory phase and are slowly being adapted in the clinic. Some scientists remain skeptical with the development of the field, and warn that there is a much larger chance that electrical prosthesis will be developed to solve clinical problems such as hearing loss or paralysis before cell therapy is used in a clinic.

Novel drug delivery systems are being researched in order to improve the lives of those who struggle with brain disorders that might not be treated with stem cells, modulation, or rehabilitation. Pharmaceuticals play a very important role in society, and the brain has a very selective barrier that prevents some drugs from going from the blood to the brain. There are some diseases of the brain such as meningitis that require doctors to directly inject medicine into the spinal cord because the drug cannot cross the blood–brain barrier. Research is being conducted to investigate new methods of targeting the brain using the blood supply, as it is much easier to inject into the blood than the spine. New technologies such as nanotechnology are being researched for selective drug delivery, but these technologies have problems as with any other. One of the major setbacks is that when a particle is too large, the patient's liver will take up the particle and degrade it for excretion, but if the particle is too small there will not be enough drug in the particle to take effect. In addition, the size of the capillary pore is important because too large a particle might not fit or even plug up the hole, preventing adequate supply of the drug to the brain. Other research is involved in integrating a protein device between the layers to create a free-flowing gate that is unimpeded by the limitations of the body. Another direction is receptor-mediated transport, where receptors in the brain used to transport nutrients are manipulated to transport drugs across the blood–brain barrier. Some have even suggested that focused ultrasound opens the blood–brain barrier momentarily and allows free passage of chemicals into the brain. Ultimately the goal for drug delivery is to develop a method that maximizes the amount of drug in the loci with as little degraded in the blood stream as possible.

Neuromodulation is a technology currently used for patients with movement disorders, although research is currently being done to apply this technology to other disorders. Recently, a study was done on if DBS could improve depression with positive results, indicating that this technology might have potential as a therapy for multiple disorders in the brain. DBS is limited by its high cost however, and in developing countries the availability of DBS is very limited. A new version of DBS is under investigation and has developed into the novel field, optogenetics. Optogenetics is the combination of deep brain stimulation with fiber optics and gene therapy. Essentially, the fiber optic cables are designed to light up under electrical stimulation, and a protein would be added to a neuron via gene therapy to excite it under light stimuli. So by combining these three independent fields, a surgeon could excite a single and specific neuron in order to help treat a patient with some disorder. Neuromodulation offers a wide degree of therapy for many patients, but due to the nature of the disorders it is currently used to treat its effects are often temporary. Future goals in the field hope to alleviate that problem by increasing the years of effect until DBS can be used for the remainder of the patient's life. Another use for neuromodulation would be in building neuro-interface prosthetic devices that would allow quadriplegics the ability to maneuver a cursor on a screen with their thoughts, thereby increasing their ability to interact with others around them. By understanding the motor cortex and understanding how the brain signals motion, it is possible to emulate this response on a computer screen.

Ethics

Stem cells

The ethical debate about use of embryonic stem cells has stirred controversy both in the United States and abroad; although more recently these debates have lessened due to modern advances in creating induced pluripotent stem cells from adult cells. The greatest advantage for use of embryonic stem cells is the fact that they can differentiate (become) nearly any type of cell provided the right conditions and signals. However, recent advances by Shinya Yamanaka et al. have found ways to create pluripotent cells without the use of such controversial cell cultures. Using the patient's own cells and re-differentiating them into the desired cell type bypasses both possible patient rejection of the embryonic stem cells and any ethical concerns associated with using them, while also providing researchers a larger supply of available cells. However, induced pluripotent cells have the potential to form benign (though potentially malignant) tumors, and tend to have poor survivability in vivo (in the living body) on damaged tissue. Much of the ethics concerning use of stem cells has subsided from the embryonic/adult stem cell debate due to its rendered moot, but now societies find themselves debating whether or not this technology can be ethically used. Enhancements of traits, use of animals for tissue scaffolding, and even arguments for moral degeneration have been made with the fears that if this technology reaches its full potential a new paradigm shift will occur in human behavior.

Military application

New neurotechnologies have always garnered the appeal of governments, from lie detection technology and virtual reality to rehabilitation and understanding the psyche. Due to the Iraq War and War on Terror, American soldiers coming back from Iraq and Afghanistan are reported to have percentages up to 12% with PTSD. There are many researchers hoping to improve these peoples' conditions by implementing new strategies for recovery. By combining pharmaceuticals and neurotechnologies, some researchers have discovered ways of lowering the "fear" response and theorize that it may be applicable to PTSD. Virtual reality is another technology that has drawn much attention in the military. If improved, it could be possible to train soldiers how to deal with complex situations in times of peace, in order to better prepare and train a modern army.

Privacy

Finally, when these technologies are being developed society must understand that these neurotechnologies could reveal the one thing that people can always keep secret: what they are thinking. While there are large amounts of benefits associated with these technologies, it is necessary for scientists, citizens and policy makers alike to consider implications for privacy. This term is important in many ethical circles concerned with the state and goals of progress in the field of neurotechnology (see Neuroethics). Current improvements such as “brain fingerprinting” or lie detection using EEG or fMRI could give rise to a set fixture of loci/emotional relationships in the brain, although these technologies are still years away from full application. It is important to consider how all these neurotechnologies might affect the future of society, and it is suggested that political, scientific, and civil debates are heard about the implementation of these newer technologies that potentially offer a new wealth of once-private information. Some ethicists are also concerned with the use of TMS and fear that the technique could be used to alter patients in ways that are undesired by the patient.

Cognitive liberty

Cognitive liberty refers to a suggested right to self-determination of individuals to control their own mental processes, cognition, and consciousness including by the use of various neurotechnologies and psychoactive substances. This perceived right is relevant for reformation and development of associated laws.

Neuropharmacology

From Wikipedia, the free encyclopedia

Neuropharmacology is the study of how drugs affect cellular function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

History

Neuropharmacology did not appear in the scientific field until, in the early part of the 20th century, scientists were able to figure out a basic understanding of the nervous system and how nerves communicate between one another. Before this discovery, there were drugs that had been found that demonstrated some type of influence on the nervous system. In the 1930s, French scientists began working with a compound called phenothiazine in the hope of synthesizing a drug that would be able to combat malaria. Though this drug showed very little hope in the use against malaria-infected individuals, it was found to have sedative effects along with what appeared to be beneficial effects toward patients with Parkinson’s disease. This black box method, wherein an investigator would administer a drug and examine the response without knowing how to relate drug action to patient response, was the main approach to this field, until, in the late 1940s and early 1950s, scientists were able to identify specific neurotransmitters, such as norepinephrine (involved in the constriction of blood vessels and the increase in heart rate and blood pressure), dopamine (the chemical whose shortage is involved in Parkinson’s disease), and serotonin (soon to be recognized as deeply connected to depression). In the 1950s, scientists also became better able to measure levels of specific neurochemicals in the body and thus correlate these levels with behavior. The invention of the voltage clamp in 1949 allowed for the study of ion channels and the nerve action potential. These two major historical events in neuropharmacology allowed scientists not only to study how information is transferred from one neuron to another but also to study how a neuron processes this information within itself.

Overview

Neuropharmacology is a very broad region of science that encompasses many aspects of the nervous system from single neuron manipulation to entire areas of the brain, spinal cord, and peripheral nerves. To better understand the basis behind drug development, one must first understand how neurons communicate with one another. This article will focus on both behavioral and molecular neuropharmacology; the major receptors, ion channels, and neurotransmitters manipulated through drug action and how people with a neurological disorder benefit from this drug action.

Neurochemical interactions

To understand the potential advances in medicine that neuropharmacology can bring, it is important to understand how human behavior and thought processes are transferred from neuron to neuron and how medications can alter the chemical foundations of these processes. 

Neurons are known as excitable cells because on its surface membrane there are an abundance of proteins known as ion-channels that allow small charged particles to pass in and out of the cell. The structure of the neuron allows chemical information to be received by its dendrites, propagated through the perikaryon (cell body) and down its axon, and eventually passing on to other neurons through its axon terminal.

Labeling of different parts of a neuron

 

These voltage-gated ion channels allow for rapid depolarization throughout the cell. This depolarization, if it reaches a certain threshold, will cause an action potential. Once the action potential reaches the axon terminal, it will cause an influx of calcium ions into the cell. The calcium ions will then cause vesicles, small packets filled with neurotransmitters, to bind to the cell membrane and release its contents into the synapse. This cell is known as the pre-synaptic neuron, and the cell that interacts with the neurotransmitters released is known as the post-synaptic neuron. Once the neurotransmitter is released into the synapse, it can either bind to receptors on the post-synaptic cell, the pre-synaptic cell can re-uptake it and save it for later transmission, or it can be broken down by enzymes in the synapse specific to that certain neurotransmitter. These three different actions are major areas where drug action can affect communication between neurons.

There are two types of receptors that neurotransmitters interact with on a post-synaptic neuron. The first types of receptors are ligand-gated ion channels or LGICs. LGIC receptors are the fastest types of transduction from chemical signal to electrical signal. Once the neurotransmitter binds to the receptor, it will cause a conformational change that will allow ions to directly flow into the cell. The second types are known as G-protein-coupled receptors or GPCRs. These are much slower than LGICs due to an increase in the amount of biochemical reactions that must take place intracellularly. Once the neurotransmitter binds to the GPCR protein, it causes a cascade of intracellular interactions that can lead to many different types of changes in cellular biochemistry, physiology, and gene expression. Neurotransmitter/receptor interactions in the field of neuropharmacology are extremely important because many drugs that are developed today have to do with disrupting this binding process.

Molecular neuropharmacology

Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, and receptors on neurons, with the goal of developing new drugs that will treat neurological disorders such as pain, neurodegenerative diseases, and psychological disorders (also known in this case as neuropsychopharmacology). There are a few technical words that must be defined when relating neurotransmission to receptor action:

• Agonist – a molecule that binds to a receptor protein and activates that receptor
• Competitive antagonist – a molecule that binds to the same site on the receptor protein as the agonist, preventing activation of the receptor
• Non-competitive antagonist – a molecule that binds to a receptor protein on a different site than that of the agonist, but causes a conformational change in the protein that does not allow activation.

The following neurotransmitter/receptor interactions can be affected by synthetic compounds that act as one of the three above. Sodium/potassium ion channels can also be manipulated throughout a neuron to induce inhibitory effects of action potentials.

GABA

The GABA neurotransmitter mediates the fast synaptic inhibition in the central nervous system. When GABA is released from its pre-synaptic cell, it will bind to a receptor (most likely the GABA_A receptor) that causes the post-synaptic cell to hyperpolarize (stay below its action potential threshold). This will counteract the effect of any excitatory manipulation from other neurotransmitter/receptor interactions.

This GABA_A receptor contains many binding sites that allow conformational changes and are the primary target for drug development. The most common of these binding sites, benzodiazepine, allows for both agonist and antagonist effects on the receptor. A common drug, diazepam, acts as an allosteric enhancer at this binding site. Another receptor for GABA, known as GABA_B, can be enhanced by a molecule called baclofen. This molecule acts as an agonist, therefore activating the receptor, and is known to help control and decrease spastic movement.

Dopamine

The dopamine neurotransmitter mediates synaptic transmission by binding to five specific GPCRs. These five receptor proteins are separated into two classes due to whether the response elicits an excitatory or inhibitory response on the post-synaptic cell. There are many types of drugs, legal and illegal, that effect dopamine and its interactions in the brain. With Parkinson's disease, a disease that decreases the amount of dopamine in the brain, the dopamine precursor Levodopa is given to the patient due to the fact that dopamine cannot cross the blood–brain barrier and L-dopa can. Some dopamine agonists are also given to Parkinson's patients that have a disorder known as restless leg syndrome or RLS. Some examples of these are ropinirole and pramipexole.

Psychological disorders like that of attention deficit hyperactivity disorder (ADHD) can be treated with drugs like methylphenidate (also known as Ritalin), which block the re-uptake of dopamine by the pre-synaptic cell, thereby providing an increase of dopamine left in the synaptic gap. This increase in synaptic dopamine will increase binding to receptors of the post-synaptic cell. This same mechanism is also used by other illegal and more potent stimulant drugs such as cocaine.

Serotonin

The serotonin neurotransmitter has the ability to mediate synaptic transmission through either GPCR's or LGIC receptors. Depending on what part of the brain region serotonin is being acted upon, will depend on whether the output is either increasing or decreasing post-synaptic responses. The most popular and widely used drugs in the regulation of serotonin during depression are known as SSRIs or selective serotonin reuptake inhibitors. These drugs inhibit the transport of serotonin back into the pre-synaptic neuron, leaving more serotonin in the synaptic gap to be used.

Before the discovery of SSRIs, there were also very many drugs that inhibited the enzyme that breaks down serotonin. MAOIs or monoamine oxidase inhibitors increased the amount of serotonin in the pre-synaptic cell, but had many side-effects including intense migraines and high blood pressure. This was eventually linked to the drug's interacting with a common chemical known as tyramine found in many types of food.

Ion channels

Ion channels located on the surface membrane of the neuron allows for an influx of sodium ions and outward movement of potassium ions during an action potential. Selectively blocking these ion channels will decrease the likelihood of an action potential to occur. The drug riluzole is a neuroprotective drug that blocks sodium ion channels. Since these channels cannot activate, there is no action potential, and the neuron does not perform any transduction of chemical signals into electrical signals and the signal does not move on. This drug is used as an anesthetic as well as a sedative.

Behavioral neuropharmacology

Dopamine and serotonin pathway

 

One form of behavioral neuropharmacology focuses on the study of drug dependence and how drug addiction affects the human mind. Most research has shown that the major part of the brain that reinforces addiction through neurochemical reward is the nucleus accumbens. The image to the right shows how dopamine is projected into this area. Chronic alcohol abuse can cause dependence and addiction. How this addiction occurs is described below.

Ethanol

Alcohol's rewarding and reinforcing (i.e., addictive) properties are mediated through its effects on dopamine neurons in the mesolimbic reward pathway, which connects the ventral tegmental area to the nucleus accumbens (NAcc). One of alcohol's primary effects is the allosteric inhibition of NMDA receptors and facilitation of GABA_A receptors (e.g., enhanced GABA_A receptor-mediated chloride flux through allosteric regulation of the receptor). At high doses, ethanol inhibits most ligand gated ion channels and voltage gated ion channels in neurons as well. Alcohol inhibits sodium-potassium pumps in the cerebellum and this is likely how it impairs cerebellar computation and body co-ordination.

With acute alcohol consumption, dopamine is released in the synapses of the mesolimbic pathway, in turn heightening activation of postsynaptic D1 receptors. The activation of these receptors triggers postsynaptic internal signaling events through protein kinase A which ultimately phosphorylate cAMP response element binding protein (CREB), inducing CREB-mediated changes in gene expression.

With chronic alcohol intake, consumption of ethanol similarly induces CREB phosphorylation through the D1 receptor pathway, but it also alters NMDA receptor function through phosphorylation mechanisms; an adaptive downregulation of the D1 receptor pathway and CREB function occurs as well. Chronic consumption is also associated with an effect on CREB phosphorylation and function via postsynaptic NMDA receptor signaling cascades through a MAPK/ERK pathway and CAMK-mediated pathway. These modifications to CREB function in the mesolimbic pathway induce expression (i.e., increase gene expression) of ΔFosB in the NAcc, where ΔFosB is the "master control protein" that, when overexpressed in the NAcc, is necessary and sufficient for the development and maintenance of an addictive state (i.e., its overexpression in the nucleus accumbens produces and then directly modulates compulsive alcohol consumption).

Research

Parkinson's disease

Parkinson's disease is a neurodegenerative disease described by the selective loss of dopaminergic neurons located in the substantia nigra. Today, the most commonly used drug to combat this disease is levodopa or L-DOPA. This precursor to dopamine can penetrate through the blood–brain barrier, whereas the neurotransmitter dopamine cannot. There has been extensive research to determine whether L-dopa is a better treatment for Parkinson's disease rather than other dopamine agonists. Some believe that the long-term use of L-dopa will compromise neuroprotection and, thus, eventually lead to dopaminergic cell death. Though there has been no proof, in-vivo or in-vitro, some still believe that the long-term use of dopamine agonists is better for the patient.

Alzheimer's disease

While there are a variety of hypotheses that have been proposed for the cause of Alzheimer's disease, the knowledge of this disease is far from complete to explain, making it difficult to develop methods for treatment. In the brain of Alzheimer's patients, both neuronal nicotinic acetylcholine (nACh) receptors and NMDA receptors are known to be down-regulated. Thus, four anticholinesterases have been developed and approved by the U.S. Food and Drug Administration (FDA) for the treatment in the U.S.A. However, these are not ideal drugs, considering their side-effects and limited effectiveness. One promising drug, nefiracetam, is being developed for the treatment of Alzheimer's and other patients with dementia, and has unique actions in potentiating the activity of both nACh receptors and NMDA receptors.

Future

With advances in technology and our understanding of the nervous system, the development of drugs will continue with increasing drug sensitivity and specificity. Structure-activity relationships are a major area of research within neuropharmacology; an attempt to modify the effect or the potency (i.e., activity) of bioactive chemical compounds by modifying their chemical structures.