History of neuroimaging

The history of neuroimaging, began in the early 1900s with a technique called pneumoencephalography. This process involved draining the cerebrospinal fluid from around the brain and replacing it with air, altering the relative density of the brain and its surroundings, to cause it to show up better on an x-ray. It was considered to be incredibly unsafe for patients (Beaumont 8). A form of magnetic resonance imaging (MRI) and computed tomography (CT) were developed in the 1970s and 1980s. The new MRI and CT technologies were considerably less harmful and are explained in greater detail below. Next came SPECT and PET scans, which allowed scientists to map brain function because, unlike MRI and CT, these scans could create more than just static images of the brain's structure. Learning from MRI, PET and SPECT scanning, scientists were able to develop functional MRI (fMRI) with abilities that opened the door to direct observation of cognitive activities.

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Early uses of brain imaging

The desire to understand the human mind has been one of the main desires of philosophers throughout the ages. Questions about thoughts, desires, etcetera have drawn psychologists, computer scientists, philosophers, sociologists and the like together into the new discipline of cognitive science. Non-invasive imaging of the human brain has proven invaluable in this context.

Structural imaging began with early radiographic techniques to image the human brain. Unfortunately, because the brain is almost entirely composed of soft tissue that is not radio-opaque, it remains essentially invisible to ordinary or plain x-ray examination. This is also true of most brain abnormalities, though there are exceptions such as a calcified tumour (e.g.meningioma, craniopharyngioma, some types of glioma); whilst calcification in such normal structures as the pineal body, the choroid plexuses, or large brain arteries may indirectly give important clues to the presence of structural disease in the brain itself.

In 1918 the American neurosurgeon Walter Dandy introduced the technique of ventriculography whereby images of the ventricular system within the brain were obtained by injection of filtered air directly into one or both lateral ventricles of the brain via one or more small trephine holes drilled in the skull under local anaesthesia. Though not usually a painful procedure, ventriculography carried significant risks to the patient under investigation, such as haemorrhage, infection, and dangerous changes in intracranial pressure. Nevertheless the surgical information given by this method was often remarkably precise and greatly enlarged the capabilities and accuracy of neurosurgical treatment. Dandy also observed that air introduced into the subarachnoid space via lumbar spinal puncture could enter the cerebral ventricles and also demonstrate the cerebrospinal fluid compartments around the base of the brain and over its surface. This technique was called pneumoencephalography. It further extended the scope for precise intracranial diagnosis, but at a similar cost of risks to the patient as well as being, in itself, a most unpleasant and often painful ordeal.

Development of modern techniques

In 1927 Egas Moniz, professor of neurology in Lisbon, introduced cerebral angiography, whereby both normal and abnormal blood vessels in and around the brain could be visualized with great accuracy. In its early days this technique likewise carried both immediate and long-term risks, many of them referable to deleterious effects of the positive-contrast substances that were used for injection into the circulation. Techniques have become very refined in the past few decades, with one in 200 patients or less experiencing ischemic sequelae from the procedure. As a result, cerebral angiography remains an essential part of the neurosurgeon's diagnostic imaging armamentarium and, increasingly, of the therapeutic armamentarium as well, in the neurointerventional management of cerebral aneurysms and other blood-vessel lesions and in some varieties of brain tumor.

Computerized tomography

With the advent of computerized axial tomography (CAT or CT scanning), ever more detailed anatomic images of the brain became available for diagnostic and research purposes. The names of Oldendorf (in 1961) Godfrey Newbold Hounsfield and Allan McLeod Cormack (in 1973) are associated with this revolutionary innovation, which enabled much easier, safer, non-invasive, painless and (to a reasonable extent) repeatable neuro-investigation. Cormack and Housenfield won the Nobel Prize in Physiology or Medicine in 1979 for this work.

Radioactive neuroimaging

Early techniques such as xenon inhalation provided the first blood flow maps of the brain. Developed in the early 1960's by Niels A. Lassen, David H. Ingvar and Erik Skinhøj in southern Scandinavia it used the isotope xenon-133. Later versions would have 254 scintillators so a two-dimensional image could be produced on a color monitor. It allowed them to construct images reflecting brain activation from speaking, reading, visual or auditory perception and voluntary movement^[1].

Soon after the invention of CAT, the development of radioligands started the functional imaging revolution. Radioligands either remain within the blood stream or enter the brain and bind to receptors. Radioligands are either single photon or positron emitters. This is how single photon emission computed tomography (SPECT) and positron emission tomography (PET) got their names. Edward J. Hoffman and Michael Phelps developed the first human PET scanner in 1973.

Functional imaging took a large step forward with the development of oxygen-15 labelled water (H₂¹⁵O, or H20-15) imaging. H20-15 emits positrons and creates images based on regional blood flow within the brain. Since active neurons recruit a robust blood supply, H20-15 PET allowed investigators to make regional maps of brain activity during various cognitive tasks. Later, a more common sort of functional imaging based on PET scans used FDG, a positron-emitting sugar-derivative which is distributed in the brain according to local metabolic activity. Unlike the short half-life of oxygen-15 (2.25 minutes), the 110 minute half-life of FDG allowed PET scans by machines physically distant from the cyclotron producing the isotope (in this case fluorine-18).

Magnetic resonance imaging

More or less concurrently, magnetic resonance imaging (MRI or MR scanning) was developed. Rather than using ionizing or x-radiation, MRI uses the variation in signals produced by protons in the body when the head is placed in a strong magnetic field. Associated with early application of the basic technique to the human body are the names of Jackson (in 1968), Damadian (in 1972), and Abe and Paul Lauterbur(in 1973). Lauterbur and Sir Peter Mansfield were awarded the 2003 Nobel Prize in Physiology or Medicine for their discoveries concerning MRI. At first, structural imaging benefited more than functional imaging from the introduction of MRI. During the 1980s a veritable explosion of technical refinements and diagnostic MR applications took place, enabling even neurological tyros to diagnose brain pathology that would have been elusive or incapable of demonstration in a living person only a decade or two earlier.

Scientists soon learned that the large blood flow changes measured by H20-15 PET were also imaged by MRI. Functional magnetic resonance imaging (fMRI) was born. Since the 1990s, fMRI has come to dominate the brain mapping field due to its low invasiveness, lack of radiation exposure, and relatively wide availability.

Physicists have also developed other MRI-based techniques such as magnetic resonance spectroscopy (for measuring some key metabolites such as N-acetylaspartate and lactate within the living brain) and diffusion tensor imaging (for mapping white matter tracts within the living brain). Whereas structural MRI and CAT scanning have a large place in medicine, fMRI and its brethren techniques are still largely devoted to neuroscience research. However, very recently neurologists have started to use fMRI to begin to answer clinical questions, such as how long after thrombotic stroke is it safe and effective to give clot-dissolving drug like tissue plasminogen activator (TPA). Similarly, PET and SPECT have moved out of neuro-research and are increasingly being used clinically to help diagnose and differentiate types of dementing illnesses (dementia).

Multimodal Neuroimaging

Multimodal imaging combines existing brain imaging techniques in ways which allow us to better interpret the data.

Besides fMRI, another example of technology allowing relatively older brain imaging techniques to be even more helpful is our ability to combine the different techniques to get one brain map. This happens quite frequently with MRI and EEG scans. The electrical diagram of the EEG provides split-second timing while the MRI provides high levels of spatial accuracy.

Anatomically-constrained Magnetoencephalography (aMEG) is a relatively new technique which was first employed in 2000 ^[2]. which combines the spatial resolution of a structural MRI scan with the temporal resolution of the MEG. ThisOften the nonuniqueness of the MEG source estimation problem (inverse problem can be alleviated by incorporating information from other imaging modalities as an a priori constraint. aMEG uses anatomical MRI data as a geometrical or location constraint and as a medium for visualization of the MEG results. MEG does not provide structural/anatomical information. Therefore MEG data often must be combined with MR data into a composite image of function overlaid on anatomy to produce activation maps. [1]

Recent Breakthroughs

Recent breakthroughs in non-invasive brain imaging have been somewhat limited because most of them have not been completely novel; rather, they are simply refining existing brain imaging techniques. fMRI is a perfect example of this from the early 1990s, and it still remains the most popular brain imaging technique available today.

Advances have been made in a number of ways regarding neuroimaging, and this section will cover some of the more prominent improvements including computational advances, transcranial magnetic stimulation, and nuclear magnetic resonance.

To begin with, much of the recent progress has had to do not with the actual brain imaging methods themselves but with our ability to utilize computers in analyzing the data. For example, substantial discoveries in the growth of human brains from age three months to the age of fifteen have been made due to the creation of high-resolution brain maps and computer technology to analyze these maps over various periods of time and growth (Thompson, UCLA). This type of breakthrough represents the nature of most breakthroughs in neuroscience today. With fMRI technology mapping brains beyond what we are already understanding, most innovators time is being spent trying to make sense of the data we already have rather than probing into other realms of brain imaging and mapping.

This can be seen more clearly in the fact that brain imaging archives are catching on and neuroinformatics is allowing researchers to examine thousands of brains rather than just a few (Lynch). Also, these archives are universalizing and standardizing formats and descriptions so that they are more searchable for everyone. For the past decade we have been able to get data and now our technology allows us to share findings and research much easier. This has also allowed for "brain atlases" to be made. Brain atlases are simply maps of what normal functioning brains look like (Thompson, Bioinformatics).

Transcranial magnetic stimulation (TMS) is a recent innovation in brain imaging. In TMS, a coil is held near a person's head to generate magnetic field impulses that stimulate underlying brain cells to make someone perform a specific action. Using this in combination with MRI, the researcher can generate maps of the brain performing very specific functions. Instead of asking a patient to tap his or her finger, the TMS coil can simply "tell" his or her brain to tap his or her finger. This eliminates many of the false positives received from traditional MRI and fMRI testing. The images received from this technology are slightly different from the typical MRI results, and they can be used to map any subject's brain by monitoring up to 120 different stimulations. This technology has been used to map both motor processes and visual processes (Potts link at bottom of TMS). In addition to fMRI, the activation of TMS can be measured using electroencephalography (EEG) or near infrared spectroscopy (NIRS).

Nuclear magnetic resonance (NMR) is what MRI and fMRI technologies were derived from, but recent advances have been made by going back to the original NMR technology and revamping some of its aspects. NMR traditionally has two steps, signal encoding and detection, and these steps are normally carried out in the same instrument. The new discovery, however, suggests that using laser-polarized xenon gas for "remembering" encoded information and transporting that information to a remote detection site could prove far more effective (Preuss). Separating the encoding and detection allows researchers to gain data about chemical, physical, and biological processes that they have been unable to gain until now. The end result allows researchers to map things as big as geological core samples or as small as single cells.

It is interesting to see how advances are split between those seeking a completely mapped brain by utilizing single neuron imaging and those utilizing images of brains as subjects perform various high-level tasks. Single neuron imaging (SNI) uses a combination of genetic engineering and optical imaging techniques to insert tiny electrodes into the brain for the purpose of measuring a single neuron's firing. Due to its damaging repercussions, this technique has only been used on animals, but it has shed a lot of light on basic emotional and motivational processes. The goal of studies in higher-level activities is to determine how a network of brain areas collaborates to perform each task. This higher-level imaging is much easier to do because researchers can easily use subjects who have a disease such as Alzheimer's. The SNI technology seems to be going after the possibility for AI while the network-probing technology seems to be more for medical purposes.

Practical achievements of functional brain imaging

In early 2000s the field of brain imaging reached the stage where limited practical applications of functional brain imaging became feasible. The main application area is crude forms of brain-computer interface.

• In 1998 scientists in Emory University, Atlanta and University of Tuebingen, Germany implanted a tiny glass electrode into the brain of a 56 year old man parayzsed after a stroke that allowed the patient to control a pointer on computer display.
• In 2000 Miguel Nicolelis from Duke University, North Carolina implanted about one hundred electrodes into brains of an owl monkey and used the recorded signals to muscles to control a robot arm. The signals were also transferred over the Internet to control a similar robot hand in MIT, 600 km from the monkey. [2]
• In 2001 researchers at the European Commission's Joint Research Centre used Adaptive Brain Interface, the system they developed to interpret the signals from a plastic cap put on the user's head with attached electrodes that picked electromagnetic signals from the brain. The user, Cathal O'Philbin, a 40-year-old paraplegic, was instructed to think about a rotating cube, moving his left arm (which is paralyzed) and relaxing mentally in between. These three distinct patterns were used to control the cursor on the screen. After several hours Mr. O'Philbin trained the system to recognize his mental states and managed to type "Arsenal Football Club" using his brain alone. [3]
• In 2002 a team of neurosurgeons from Brown University, Rhode Island implanted electrodes in the brains of three macaques. The chips with 7 to 30 electrodes were implanted into the motor cortices. The scientists calibrated the chips when the animals used joysticks to play a computer game, then disconnected the joysticks and used the signals intercepted by the electrodes to control the object on the screen directly. [4]
• In 2004 a team of scientists from California Institute of Technology demonstrated decoding of high level cognitive brain signals, when they managed to predict where the monkeys were planning to reach in their visual field and also what reward (water or juice) the monkeys expected to receive. The monkeys were trained to think about the particular point they were planning to reach without looking there during the experiments. [5]

Future implications

In order to best present the implications of new and better developed brain imaging technologies, it will be easiest to evaluate the implications under the categories of medicine, law, and education. When the increased possibility of mapping brains at the neuronal or cellular level is coupled with the increased possibility for nanotechnology, the results can be very striking. Our ability to understand the brain could both be aided by and of aid to nanotechnology. Autonomous nanotech devices could disperse to defined locations in the brain and could be used as sensors for reporting back new information, or they could be used to eliminate unwanted cell types such as tumors.

Tumors of the brain often have a tendency to grow between normal cells and are thus quite invasive and difficult to fully eradicate. Devices can be designed to recognize tumorous cells and selectively destroy them with some sort of toxin. They can be guided to the tumor mass by using information gathered from fMRI technology, and as mentioned above, they could remain in place to act as sensors for reporting back new information. People with seizures are another good example of something that could be helped with this technology. Blindness resulting from eye disease may be correctable by replacing the eye with a nanotechnological equivalent. Optobionics Corporation has already successfully tested its silicon retina on patients with damaged retina cells (Hook). The scenarios where this could come into play seem almost endless. FMRI technology is already allowing the completion of surgeries that were once thought unimaginable (Schulder). Many risky brain surgeries are performed via computerized images of brains by the surgeons, and then carried out on the patient by means of smaller, less invasive mechanisms.

Closer on the horizon than the above-mentioned nanotechnologies would be the possibility for researchers to locate specifically where various diseases are located in the brain and to figure out exactly what is going on. Scientists and doctors are only now beginning to understand where exactly Alzheimer's disease takes effect and what it is that Alzheimer s does. Other examples of diseases helped by brain imaging are Parkinson's disease, Lyme disease, schizophrenia, and depression.

The way we teach children may also be impacted by new brain imaging technology. Imaging has confirmed the theory that loving parents make smarter, happier babies, and that talking and playing with a baby and letting him or her see, touch, smell and hear new things will help develop the brain's hardwiring (Zwillich). New teaching techniques could be developed based upon what brain imaging research tells us about how the brain reacts to learning various types of things. Also, if we understand all the functions of the various sections of the brain, it is very possible that we could augment the brain through surgery or nanotechnology to give people special abilities in practically any area.

With everything new in society there are always legal issues and the possibilities stemming from brain imaging are no exception. For starters, imaging has shown that multiple brain areas are often dysfunctional in criminals. In psychopaths, the amygdala is not activated by emotional stimulus (Swiercinsk). Many criminal defense lawyers now use brain imaging in the defense of their client. There are many questions brought up by this including the question of whether or not someone should be forced to submit to a brain scan if his or her brain can be stimulated in such a way that it can be determined what, if any, crimes that person is guilty of. Of course the scenarios like this are unlimited in number. Questions of how the law should limit TMS activity and the ethical implications of that are sure to arise as well.

The expediency with which scientists and researchers are able to fully understand a completely mapped human brain will directly determine the arena of discussion in neuroscience, philosophy, and all of cognitive science for years to come. A completed neuroscience would have far reaching potential implications, including direct mind-computer interface, technologically assisted telepathy and mind transfer. By looking at some current technologies, recent breakthroughs in brain imaging, and some of the implications of brain imaging, this article has barely begun to tip what is building up to be an enormous iceberg.

References

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Notes

1. ^ Niels A. Lassen, David H. Ingvar, Erik Skinhøj, "Brain Function and Blood Flow", Scientific American, 239(4):50-59, 1978 October.
2. ^ Dale AM, Liu AK, Fischl B, Lewine JD, Buckner RL, Belliveau JW, Halgren E (2000) Dynamic statistical parameter mapping: combining fMRI and MEG to produce high resolution imaging of cortical activity. Neuron, 26: 55-67.