Brain-Computer-Interfaces

NeuroprosthesesDe maakbare mens: thuisopdracht

2/9/2009Dominic Portain

Introduction

The most incomprehensible thing about the world is that it is comprehensi-ble.

Albert Einstein1

The central nervous system is virtually the most influential physiological system in a human body. Several nerves contact every organ and every extremity. Almost every bodily function is initiated and modulated by a nearby cluster of neurons. These accumulations are themselves controlled by the central control system, the human brain.

About 1012 nerve cells2 account in this place for the majority of the nervous sys-tem. Every neuron builds an activation potential and “fires” this signal along the main output line – its axon. This process is repeated several times per second, re-sulting in a unique firing frequency. Neurons accept several types of input signals to change this base rate, mainly via several connection points on the widely branched dendrites – the signal input pathways. An overview over the variety of neurotransmitters and signal transportation forms suggests that there are two different types of interneuronal connections: excitatory and inhibitory synapses. Where excitatory signals are increasing the firing rate of one neuron, activation from an inhibitory connection results in the opposite effect.

During the existence of a neuron, several factors can threaten the proper func-tion of signal processing. Physical stress is the main cause that results in torn nerve pathways. In the case of a severed dendrite, the injury disconnects the cell body from some of their input and control signals. If the neuron is a part of a func-tional system, axon injury ceases the nerve cell from sending impulses to peripheral organs or adjacent neuron clusters.

Because excitation of a neuron would be possible through an external stimulus, a damaged neuron could theoretically be replaced - or at least mimicked - by an electrical stimulator. However, because the targeted neuron has been embedded in a complex network of neurons, including a variety of electrical and chemical con-nections, as well as feedback and control mechanisms, it would be difficult for cur-rent technology to replicate the complete behavioral spectrum of a damaged neu-ron. On the other hand, just because the effect of crude electrical stimulation tends to propagate on a multitude of pathways, it might be possible to re-enable excita-tory or inhibitory impulses to stimulate healthy tissue areas again. Because of the “all-or-nothing” rule, it is sometimes possible to restore the functionality of a dam-aged neuronal network with just one active contact point. It explains that the lack of a single from thousand input signals can mean the neuronal threshold can no longer be reached. Action potentials are no longer formed, and as a result, this particular neuron is seen as “silent” by their successors – a circumstance that dis-ables the whole network. If the missing input is replaced by a steady impulse, regu-lar action potentials can again be produced without significant disturbance from the artificial stimulation.

1 Vallentin A (1954) Einstein: A Biography, p. 24.2 Poliakov GI (1972) Neuron Structure of the Brain. Harvard University Press, Cambridge, Mass

2 Ethical implications

Implementation

If you would understand anything, observe its beginning and its develop-ment.

Aristoteles

Hearing implantsIn the beginning phases of neurobiological science in the late 1960, it still

deemed impossible to reactivate a lost cognitive function by applying electrodes to existing nervous tissue. Only two decades after the first successful experiment, already 200’000 deaf people are using cochlear implants, where 80-90% of them are able to recognize and understand daily speech3. The success of these devices relies on the Volta effect, found by Alessandro Volta in 1800. It presumes that elec-tric impulses stimulating auditory regions (inner ear or according brain areas) produce audible noises without the necessity of actual sound waves. In the year 1930, this effect was rediscovered and labeled as “electrophonic hearing”4. After successful experiments with a cats’ hearing nerve, the two scientists concluded that the human auditory system was founded on electrical impulse propagation. At this time, a telephone infrastructure had already been established, and the discov-ery of the striking similarity between the cochlea and an electric microphone was a strong motivational factor in the then little research on the field of neural audition. Further attempts concentrated strongly on the transfer of sound information with-out the support from the middle or even inner ear. By relying only on electric signal propagation, it would be easily possible to bypass damaged mechanical structures that result in a permanent hearing loss.

These findings depict the foundation for the first auditory processor that split environmental sound into its different frequencies and activated an array of 23 electrodes, which were mounted directly on the auditory nerve, accordingly. The patient, treated by the French otologist and physicist Eyries in 1957, could hear sounds and understand speech fragments5, and the basic principle is still used today in basic cochlear implants. After a period of skepticism - mainly due to the patients not being able to understand speech - clinical trials in 1971 first showed positive results6. Consequently, multichannel electrodes gained on popularity and commercial interest.

In 1979, and barely noticed first, the two surgeons William House and William Hitselberger had a breakthrough in their clinic in Los Angeles. After having pushed an electrode directly into the brainstem, electric impulses were able to stimulate the hearing nucleus directly7, despite the fact that both auditory nerves were de-stroyed. This new hearing aid technology called the auditory brainstem implant proved as reliable as the already established cochlear implant, and is still in use today in case of severe nerve damage. Reliability and safety of both technologies significantly improved when signals were transmitted over a magnetic coil in the mid 1980s, eliminating common problems such as plug failures or infections.

3 Illg A, von der Haar-Heise S, Goldring JE, Lenarz T (1999) Speech perception results for children implanted with the CLARION cochlear implant at the Medical University of Hannover. Ann Otol Rhinol Laryngol suppl 177:93-984 Steven SS, Jones RC (1939) The mechanisms of hearing by electrical stimulation. J Acoust Soc Am 10:261-2695 Djourno A, Ayries C (1957) Prothèse auditive par excitation électrique à distance du nerf sensorial à l’aide d’un bobinage inclus à demeure. Presse Méd 35:1417-14236 Michelson RP (1971) The results of electric stimulation of the cochlea in human sensory deafness. Ann Otol Rhinol Laryngol 80:914-9197 Edgerton BJ, House WF, Hitselberger W (1982) Hearing by cochlear nucleus stimulation in humans. Ann Otol Rhinol Laryngol suppl 91 (2 Pt 3):117-124



Visual implantsAlthough the first experiments with visual perception implants started at the

same time as those for implanted hearing aids, this branch of applied neuroscience had to overcome greater hurdles. The main reason for the lag in clinical application is the considerable higher amount of active connections necessary to achieve an equal sensory experience: while a healthy auditory nerve transfers impulses from about 30’000 receptor cells, the visual pathway accumulates information from over 130’000’000 photoreceptors in the retina.

The early trials with direct stimulation of the visual cortex were not very suc-cessful. Participants experienced to the electrical stimulation as phosphenes - short-lived light spots – that occurred in varying locations, independent from actual light sources in the environment8. Even with considerable progress using modern multi-electrode arrays9, these implants not even provide crude outlines of the envi-ronment, leaving patients unable to find visual cues relevant for orientation. The main reason for this effect is the nonconformity of the layout in the primary visual cortex: it does not match the spatial location of retinal photoreceptors. Direct stim-ulation of the optic nerve is today only possible in a very low spatial image resolu-tion, mainly because the equivalent electrodes have to be built in extremely small dimensions. Because of the structural layout of the human eye, research about two implementations of visual implants has gained in popularity since the 1990s: epiretinal and subretinal implants.

Epiretinal implants share their technological foundations with the auditory brainstem implant. Environmental visual input is being recorded through a small camera, either external or integrated in the eye lens10. The resulting signals then are converted by a microprocessor into neural frequencies, either inhibiting or exciting the perceiving neurons on top of the retina. A clear limitation of this sys-tem lies in the structural organization of the retina. Because light impulses nor-mally would pass a cascade of different neuron clusters, signals at the last stage (where the electrodes would stimulate) do not represent a simple scheme of light-ness and darkness any more, and can only provide rough approximations to the natural scheme of activation levels and summation potentials. According to recent findings, the according image after these early post-processing steps would show extremely exaggerated edges. A common principle of color-coding is not elaborated yet, which is why all artificial imagery is rendered in shades of grey.

Subretinal implants are able to bypass photoreceptors11 (which are actually located behind the retina) by sending artificial impulses to the input layer of the intraretinal neural network. The implant usually has the form of a microchip with one photosensitive and one output side, and has to be placed in front of the layer with photoreceptors to ensure proper signal propagation. Two major problems arose for the subretinal implant. Biodegradation always becomes relevant as a silicon substrate is being enclosed in a biodynamic environment. The retina has shown to accept the foreign body quite well, but the chip tends to take long-term damage from the direct contact with living tissue. The other challenge is the miss-ing power supply. Light signals carry to little energy to power the signal processing and electric stimulation, and bodily energy sources cannot be drained yet. Promis-ing solutions for both problems have recently been developed. Energy supply is currently guaranteed by using an external (and invisible) infrared light source, and

8 Brindley GS, Levin WS (1968) The Sensations produced by electrical stimulation of the visual cortex. J Physiol 196(2):479-939 Warren DJ, Normann RA (2003) Visual neuroprothesis. Handbook of neuroprosthetic methods. Finn WE, LoPresti PG (eds) CRC Press, London, pp 261-30710 Weiland JD, Liu W, Humayun MS (2005) Retinal prosthesis. Annu Rev Biomed Eng 7:361-40111 Rizzo JF 3rd, Wyatt J, Humayun M, de Juan E, Liu W, Chow A, Eckmiller R, Zrenner E, Yagi T, Abrams G (2001) Retinal prosthesis: an encouraging first decade major challenges ahead. Ophthal-mology 108(1):13-14


biologically stable envelopes ensure the long-term structural integrity of the mi-crochip substrate12.

12 Zrenner E (2002) Will retinal implants restore vision? Science 295(5557):1022-1025


Brain-Computer InterfacesConnecting an electronic device to the human brain not only to provide sensory

input but also to influence actual behavior is a practice that goes back to the 1950s. By installing electrodes in the cerebral cortex of humans and animals, it was possi-ble for José Delgado from Yale University to evoke or attenuate a variety of reac-tions13. Surprisingly, not only motor responses but also primal feelings of fear or aggression could be provoked by electric stimulation14. The researcher suggested in 1952 that this practice could be useful with therapeutic treatment of psychotic patients, and proposed in 1967 a device for remote controlling of emotional states15. Following the scheme of external behavior control, another brain stimula-tion project accidentally showed the function of the “reward center” in the hypotha-lamic region of the rat16.

The ways in which the neural networks are stimulated have gone a long way since the early days of electrical brain stimulation. In contrast to the insertion of metal needles into the brain, it is nowadays possible to view frequency patterns in real time and gently manipulate certain activation thresholds, without the device even touching the head. This technique which relies on computer controlled, super-conducting magnet coils is called deep brain stimulation.

Generally, every device that is able to measure neural activity as well as to influ-ence it could be called a human-computer interface. Typically, it consists of three modules17: Data acquisition (electrodes collecting input from the brain), signal interpretation (determining the adequate action from the incoming data) and out-put module (which executes the action).

Considering the first module, current devices can be placed in one of the two categories: invasive and non-invasive. Non-invasive technology describes every implementation where the data acquisition takes place outside the skull, i.e. through EEG measures. Because the placement of electrodes is an easy task, this type of data acquisition allows a high amount of different test subjects per period while the execution costs stay low. The biggest advantage turns out to pose a chal-lenge considering the quality of measurement. On the brain surface, several thou-sand clusters of neurons provide different frequencies at the same time. Because of a skull thickness of 6 to 12 mm, this variety of signals becomes strongly attenuated and filtered by bone with irregular electrical conduction properties. When search-ing for anomalies in form of a conscious impulse, brain signals in this condition seem to show very high noise levels. Accounting for these factors, much computing power and strong, repeated signals are needed to form a certain decision. In cur-rent BCIs on non-invasive basis, it is possible for a trained subject to choose one letter from the alphabet every two seconds on average, assuming constant full concentration on the task.

If a direct intervention should be necessary, as it is the case with epilepsy pa-tients, the neurosurgeon places several small electrodes on the surface of the brain after opening the skull. This form of data acquisition is called electrocorticography (ECoG), and the accuracy of the gained data tops non-invasive methods by several magnitudes18. This data is used by the clinic for gaining pre-surgical information

13 Delgado JM (1952) Responses evoked in waking cat by electrical stimulation of motor cortex. Am J Physiol 171(2):436-44614 Delgado JM, Rosvold HE, Looney E (1956) Evoking conditioned fear by electrical stimulation of subcortical structrues in the monkey brain. J Comp Physiol Psychol 49(4):373-38015 Delgado JM (1967) Aggression and defense under cerebral radio control. UCLA Forum Med Sci 7:171-19316 Olds J (1956) A preliminary mapping of electrical reinforcing effects in the rat brain. J Comp Physiol Psychol 49(3):281-28517 Friehs GM, Zerris VA, Ojakangas CL, Fellows MR, Donoghue JP (2004) Brain-machine and brain-computer interfaces. Stroke 35(11 suppl 1):2702-270518 Levine SP, Huggins JE, BeMent SL, Kushwaha RK, Schuh LA, Rohde MM, Passaro EA, Ross DA, Elisevich KV, Smith BJ (2000) A direct brain interface based on event-related potentials. IEEE Trans Rehabil Eng 8(2):180-185


about the condition of the specific epilepsy, and almost every invasive BCI nowa-days is a by-product of neurosurgical evaluation.


Limitations

Never measure the height of a mountain, until you have reached the top. Then you will see how low it was.

Dag Hammarskjold

The general disadvantage of implants in contrast to other methods of cognitive restoration or even enhancement is obvious: this implementation always requires surgery. To understand why, despite the great amount of professional expense, neural implants are still considered today as veritable option for treatment, I will list the most important reasons in favor for implanted implementations.

Unobtrusive: Can be placed under the skin or skull without limiting technical func-tionsConnectivity: Restoration of neural functions is possible even with missing essential elementsContinuity: Continuous function is ensured without any attention from the patientControl: Desired effect can be varied or shut off immediately

ProblemsRegarding current treatments, especially in the sector of epilepsy, these factors

clearly put implants in favor towards drug-based therapies. However, to put the advantages in relation, a closer look towards the current limitations concerning neural implants will be necessary.

Despite cochlear implants being successfully improved over the last 40 years and neural vision aids reaching the verge of clinical application, there is still no possibility to restore one of the other senses. Moreover, even current devices can only deliver very poor sensory information quality. Cochlear audio quality is compa-rable to a mobile with bad reception. The image from a visual implant is as blurry as under water, insensitive to low light and appears only in shades of grey. This limitation of quality is mainly due to the small number of electrodes in an estab-lished connection with functional tissue, and current research addresses this prob-lem with larger electrode arrays providing a much higher contact point density19.

Even if the connection between the signal processor and brain is approaching perfection, patients that are treated with this implant either have lost their sensory input in beforehand or were even born without it. Neuroplasticity is a general process in the human brain, which tends to strengthen heavily used connections and degenerate those that are scarcely active. Especially when nerve fibers are severed due to physical stress, which is often the case with spinal cord injuries, neural activation on the peripheral side of the nerve stops completely and causes rapid nerve degeneration. Even with constant electrical stimulation or with the help of protective substances, the complete connection cannot be assured because of a process called glial scarring. After the first few months in the life of a brain, a connection between every possibly important brain region is established via axons. After the nerve growth hormone wears off, the structural cells effectively prevent growth of new nerve fibres with physical and chemical barriers. When a child is born, its brain is in fact equipped with so many connections that most of them con-tradict each other. Neuroplasticity and constant exercise with the environment initiate the degeneration of unnecessary axons, making it finally possible for the

19 Fernandez E, Ferrandez J, Ammermuller J, Normann RA (2000) Population coding in spike trains of simultaneously recorded retinal ganglion cells. Brain Res 887(1):222-229


child to move both hands apart from each other. The possibility for injured axons to regrow again, especially with old connections over long distances, is low – decreas-ing the usefulness of an implant effectively.

Not only nerve connections, but also electrode matter suffers from degradation over time. Tissue rejection may cause the creation of an isolating layer of scar cells, or electric stimulation could even damage the target neurons through injudicious use. The current goal is thus to ensure the biocompatibility of neural implants.

Finally, the electrode array in combination with the electrical stimulation soft-ware is only simulating one aspect of a healthy neural network, which is shaped from the use of various neurotransmitters and permanent learning effects through chemical and biological means. To improve the performance and reliability, to-gether with possible neural feedback, an implant should probably connect to exist-ing tissue in a more natural way. With the current toolset of methods from electri-cal and biomechanical engineering, it is hard to imagine how a highly associated electrochemical network of thousands of synapses could possibly be replaced by an artificial device. Ideally, the electronic circuit would excite and inhibit all of the adjacent neurons in the same pattern as the original neural network. To adjust for the different input conditions, “bioinspired” systems20 could translate certain in-coming environmental signals into excitation patterns, copying the known physio-logical task of the preprocessing neural network with arithmetic instructions. Espe-cially in auditory and visual perception, this setup could dramatically improve the sensory quality. A major drawback in this design involves the necessary electrode sizes to contact all neurons on a certain surface. A density of several thousand contacts per cubic millimeter is hardly imaginable in the context of nowadays ca-ble-controlled arrays. Instead, it would be possible to connect only to a small num-ber of neuron groups on both input and output sides. A signal processor would compare the input activity pattern with a limited set of data entries and translate the arrangement into a predefined output pattern, ultimately simulating all major reactions of a complex neural network. This is the level on which technological and clinical application operate today. Several factors crucial for cognitive enhance-ment such as high reaction speeds, use of neurotransmitters or only a system com-plexity density exceeding an existing neural network are still not addressable by current technology. The very basic problems of neuroelectronic implants, such as size, energy supply and biocompatibility seem to be solved by progress in material or computer sciences during the next few decades. That leaves neuroscientists to concentrate on very specific problems, and to try the most promising approaches on the way to an ingenious solution.

ApproachesCurrently, the most limiting factor with a BCI is certainly interaction speed. It is possible to improve the performance even without changing the hardware itself. Through creative interfaces that try to predict the users’ actions and in combina-tion with a high-performance 96-pin electrode, it is possible to increase the letter selection speed to less than 1.2 seconds21.

Generally, researchers in the area of neural interfaces currently follow two ap-proaches.

One possibility of improving the results is to strive for a deeper understanding of the role of small neural networks in the signal processing chain. Recent research concerning the structural composition of 117 neurons in the relay station of the visual processing pathway22 would be an example for a successful pursuit of the first approach. This brain area is directly connected to the optic nerve, and neurons 20 Fernandez E, Pelayo F, Romero S, Bongard M, Marin C, Alfaro A, Merabet L (2005) Development of a cortical visual neuroprothesis for the blind: the relevance of neuroplasticity. J Neural Eng 2(4):R1-R1221 Santhanam G, Ryu SI, Yu BM, Afshar A, Shenoy KV (2006) A high performance brain-computer interface. Nature 442(7099):95-198


are highly specialized against certain visual features. After mapping the specific role of every neuron, researchers were able to reconstruct a natural image by “lin-ear decoding” the preprocessed neural output. Similar breakthroughs recently occurred in the field of voluntary movement23 and auditory perception24.

The second approach includes the knowledge about neurophysiological systems which have already been studied intensively. Through a process called “neural morphing”, an attempt is made to construct an electronic model of the cell net-work. Simplifications are made whenever necessary; and because an engineer can build the model from scratch, even significant design improvements are possible – such with as the artificial retina “Visio1” built at the University of Pennsylvania25.

Enhancement While treatment of patients with damages in sensory nerves has been the main

motivation for extensive research on the area of neural implants, the possibility to destroy nervous tissue at the same has time been the main contradictor against the application in healthy individuals. However, as soon as efficient devices for electro-chemical stimulation become available, the successor of therapy may indeed be enhancement. Currently, most sorts of cognitive enhancement are being accom-plished by careful drug use. Coffee is a prime example of a commonly accepted drug that puts the user in control over his own wakefulness. In addition, off-label prescription drugs are used by students and high performers to regulate their sleep cycles and remain focused for longer periods. The definition of ‘enhancement’ is not fixed yet, neither socially or academically. From the council of bioethics origi-nates the statement that “’enhancement’, by contrast [to therapy], is the directed use of biotechnical power to alter, by direct intervention, not disease processes but the ‘normal’ workings of the human body and psyche, to augment or improve their native capacities and performances”. Most scientific authors separate between therapy and enhancement by the actual context of implant use, where the improve-ment of condition counts as therapy goal setting. Healthy persons with neural im-plants would thus fall into the category of enhancement. However, this distinction only works as long as implants are not yet able to outperform their natural counter-parts. From this moment on, i.e. having “only” a natural hearing sense would clas-sify for therapy. To discuss the next section, I’d like to go along the lines of Eric Juengst26: “[The term ‘enhancement’ characterizes] interventions designed to im-prove human form or functioning beyond what is necessary to sustain or restore good health”.

22 Stanley GB, Li FF, Dan Y (1999) Reconstruction of natural scenes from ensemble responses in the lateral geniculate nucleus. J Neurosci 19(18):8036-804223 Fogassi L, Luppino G (2005) Motor functions of the parietal lobe. Curr Opin Neurobiol 15(6):626-63124 Ohl FW, Scheich H, Freemann WJ (2000) Topographic analysis of epidural pure-tone-evoked poten-tials in gerbil auditory cortex. J Neurophysiol 83(5):3123-313225 Zaghloul KA, Boahen K (2004) Optic nerve signals in a neuromorphic chip: Outer and inner retina models, testing and results. IEEE Trans Biomed Eng 51(4):657-67526 Juengst ET (1998) What does enhancement mean? In Parens E (ed) Enhancing Human Traits: Ethi-cal and Social Implications. Georgetown University Press, Washington, DC:29-47


Ethical implications

There are no facts, only interpretations.Friedrich Nietzsche

The role of modern medicine seems to have taken a relatively stable balance between pharmaceutical progress and social acceptance. Following the “Normal Function Model”, it seems that the actual medical consensus consists of the goal to provide people with “normal” function to allow “equal” opportunities for every member of humanity27. As both definitions of “normal” and “health” are subject of ongoing debates, this fact should not be strongly relied on. Two main variables have to be considered when predicting ethical implications on society: the risk-ben-efit relation and the availability.

With current, socially accepted implants as with a pacemaker, there is no medi-cal doubt that the benefits of implantation outweigh the potential risks. However, with the increasing public availability of future neural prostheses, two aspects are taken into closer consideration.

Firstly, interference with adjacent neuron clusters. As a rather simple device such as the cochlear implant is used to propagate signals into the main auditory nerve, no interference with other cognitive functions would be expected - the im-plant only bypasses the middle and inner ear mechanisms. In case of a destroyed auditory nerve, the electrodes are already contacted directly with brain matter – in this case, one small neuron cluster near the spinal cord. This area is a densely pop-ulated zone, and because of two effects, this basic modification already results in a weak interference effect. The electric impulse from the electrode, meant to stimu-late nearby neurons, has to be one or two magnitudes higher than usual neural activation potentials because of the missing synapse connection. Because the space between neurons is filled with liquid, this impulse is able to propagate further than its intended working radius. In a certain distance, the voltage is not high enough to provoke a direct reaction, but potential activation levels from adjacent neurons are certainly increased during the impulse period. The second effect can be explained by the chaotic connection layout between different neuron clusters. If two neurons are located in a small distance from each other, probability is high that at least one synapse connection exists – even if it is scarcely used because both neurons belong to different task processes. Electric stimulation of this one cluster will in this case cause these few connections to be activated, especially because the base potential is already elevated. Indeed, reports from patients with auditory brainstem implants support these findings with statements of “vibration” or “nausea” when their im-plants were activated the first time28. Adjacent nuclei to the hearing pathway would be the balance system and the somatosensory system (sensation of vibration), amongst others. The higher the manipulated cognitive function, the more careful one should examine potential cognitive interferences, because an elevated base potential in higher regions would have significant and unpredictable effects on essential details of the own self – memory, object recognition, or even personality.

Finally, neurotransmitters. Only because current stimulation occurs on an elec-tric way, that does not mean the effect on the affected neurons has to be purely electric in nature. Because neurons are embedded in a network from electrical, biological and chemical reactions, it is rather very unlikely that they would not react differently, when two of these components are missing. In addition, the exact

27 Daniels N (2000) Normal functioning and the treatment-enhancement distinction. Camb Q Healthc Ethics 9:309-32228 Otto SR, Brackmann DE, Staller S, Menapace CM (1997) The multichannel auditory brainstem implant: 6-month coinvestigator results. Adv Otol Rhinol Laryngol 52:1-7


roles of the over 60 different neurotransmitters, not to speak of intermitting glia cells, are largely unknown to current science. At this moment, is it thus not possi-ble to determine potential long-term effects from artificial neural stimulation. Even the smallest of chemical interventions could influence processes we do not under-stand yet – such as attention and arousal.

Before these issues are not resolved yet, both medical and social acceptability of neural implants will be nonexistent, leaving it again to eager scientists to prepare the ground for further discussion about a promising technology.


Health & Medicine

Brain-Computer-Interfaces