In February 2002, the first patient received an epiretinal implant at the Keck School of Medicine at the University of Southern California. After that five more patients had implanted a single prosthesis in their "worse eye" by ophthalmologist Mark Humayun and his group, supported by (among others) the Department of Energy and a Californian branch of the New York based medical company "Second Sight". Their data showed that all patients for between 5 and 33 months were able to locate the position or count the number of high contrast objects with 74 to 99 percent accuracy. Furthermore, they could discriminate simple shapes, i.e. figure out the spatial orientation of a bar or the capital letter L with 61 to 80 percent accuracy (Humayun et al. 2005). Motion of light sources could also be detected by the patients. Similar results were obtained by a multi-centre study, led by Richard (Hamburg, Germany), with 19 out of 20 patients in acute tests of a retinal electrode (Feucht et al. 2005). Humayun and "Second Sight" recently announced that their 16-channel implant will be replaced by a 64-channel version in 2011.

The subretinal implant - a silicon chip 2 mm in diameter loaded with 5,000 photodiodes that is supposed to replace the retinal receptors and leave the other layers of the retina for signal processing - has been implanted in six patients from 2000 through 2002 by the American group under Chow. The authors reported that "during follow-up that ranged from 6 to 18 months, all ASRs (ASR stands for "Artificial Silicon Retina") functioned electrically". No patient showed signs ofimplant rejection, infection, inflammation, erosion, neovascularisation, retinal detachment, or migration. Visual function improvements occurred in all patients and included unexpected improvements in retinal areas distant from the implant" (Chow et al. 2004). Although Chow and colleagues have implanted the chip in another twenty patients since then, it is this latter part of their publication that continues to raise doubts about the functionality of their device. It is also doubtful whether the current generated by the photodiodes on the chip is sufficient to excite any adjacent neuron at all.

A German group led by Zrenner has designed a subretinal implant featuring an additional external power supply and a CMOS chip capable of delivering the whole range of light intensity that is visible to man. Currently, the subretinal implant of the Tübingen group contains 40x40 elements on a 3x3 mm chip. It is presumed to be capable of providing a spatial resolution of 0.6 degrees, a visual field of about 12 degrees and a visual acuity of 0.1. A clinical trial with eight blind patients is being prepared for this year.

Cortical visual implants have progressed to a point where discrimination of shapes and localisation of objects appears to be an achievable goal, allowing for a rough orientation of the patient in the environment (Fernandez et al. 2005). However, a variety of questions regarding biocompati-bility, durability, safety and physiological signal processing remains to be solved before a cortical visual neuroprosthesis could be introduced into clinical routine.

Active implants are now under development with the aim to multiplex the stimulus output and allow remote functional assessment and adjustment of the bioelectrical interface by telemetric means. While premature enthusiasm with respect to clinical applications has inspired false expectations in the past, research in this field is now progressing more slowly and steadily. Currently, most researchers anticipate that an implant will probably not fully restore vision, but rather may allow a blind person to move freely in a familiar environment, guided by visual perception of contours, outlines, and shades of light. Combined with a partial restoration of reading capabilities, this would result in a substantial improvement in the quality of life of a blind patient.

3.3.3 Human-computer Interface (HCI)

Giving paralysed patients mental control of robotic limbs or communication devices has long been a challenge for those working to free such individuals from their locked-in state. Until only a few years ago, extracting signals directly from the brain to control robotic devices has been a science fiction motif. In 1999, John Chapin's research group at the University of Philadelphia succeeded in using simultaneous recordings from large ensembles of neurons to control an external robot arm online in real time (Chapin et al. 1999). The researchers had trained rats with microelectrodes implanted in the cerebral cortex to press a lever to obtain water. Special software was designed that used mathematical transformations, including neural networks, to convert multineuron signals into "neuronal population functions" (or "population vectors") that accurately predicted lever trajectory. These functions were electronically converted into real-time signals to control a robot arm that also pulled the lever to release water. When this robot arm was switched on, 4 of 6 animals (those with > 25 neurons from which task-related activity could be derived) routinely "used" brain-derived signals to position the robot arm and obtain water. With continued training in this "neurorobotic" mode, at times the animals did not even actually carry out movement to pull the lever anymore, but "relied" completely on their brain signals and the robotic arm to supply water. At the same laboratory it was shown that it is also possible to use electrical brain stimulation to deliver "virtual" tactile cues and rewards to freely roaming rats to remotely instruct the animals to navigate through complex mazes and natural environments they have never visited before (Talwar et al. 2002).

After John P. Donoghue (Brown University, Rhode Island) (Donoghue 2002) had created a BCI by implanting electrodes in monkey brains to control the movement of a cursor on a computer screen, Miguel Nicolelis' team at Duke University in North Carolina took the control of robotic devices "by thought alone" to the next level by transmitting signals from a primate's motor cortex over a distance of 600 miles to an artificial arm (Nicolelis 2001; Donoghue 2002; Nicolelis and Chapin 2002; Nicolelis 2003). Andrew Schwartz from the University of Pittsburgh trained a monkey to feed himself by a robotic hand operated by the animal's electrical brain activity (Schwartz 2004).

From the Graz BCI group led by Gert Pfurtscheller we know that non-invasively derived brain activity can be transferred through amplifiers and leads to the muscles in the paralysed arm of a patient (Functional Electric Stimulation = FES), bypassing the damaged neuronal pathways (Pfurtscheller et al. 2003b). As a consequence of these very rapid developments, within a few years the first paralysed patients have been implanted with electrode arrays in their motor cortex, starting June 2004 at Duke University with a project funded by the central research and development organisation for the U.S. Department of Defence, the Defence Advanced Research Projects Agency (DARPA) with $26 million. Beyond treatment of paralysed patients, the project seeks to develop new technologies for augmenting human performance by accessing the brain in real time and integrating the information into external devices.

The physiological basis of BMI, electrical potentials derived from the brain, can be varied. EEG electrodes, which are attached to the scalp and pick up local field potentials (Mehring et al. 2003), slow brain activity (Bir-baumer et al. 2000) or changes in rhythmic EEG activity (Pfurtscheller et al. 2003a; Fabiani et al. 2004), can be used as an alternative to invasive electrodes placed on the surface of the brain or penetrating into brain tissue. The advantage of invasive BMIs is that they utilise localised and fast neuronal electrical activity - action potentials - lasting only about 1 millisecond. With these implants, quadriplegic patients are enabled to control a computer cursor fast and very precise, a result that had previously been achieved in monkey experiments (Donoghue 2002).

Recently, an interdisciplinary group has published on the performance of the first patient implanted at the Duke University with a 96-electrode array penetrating into the so-called "arm knob", an area in the brain's motor cortex that controls movement of the arm and the hand (Hochberg et al. 2006). The 25-year-old male patient had sustained a knife wound in 2001 that had completely transected his spinal cord at a higher cervical (C3-C4) level, resulting in complete tetraplegia. With the electrical brain activity generated by intended hand movements and the interface, which has also been called a "neuromotor prosthesis" (NMP), he underwent almost 60 recording sessions during nine months. Special decoders allow the patient to open simulated e-mail and operate devices such as a television set, even while conversing. He can also open and close a prosthetic hand, and perform simple actions with a multi-jointed robotic arm.

At this point, it appears that a market has emerged for BCIs, BMIs and their components. The company involved in the clinical trials at Duke Uni versity - Cyberkinetics, Inc. - is planning to develop a commercially available system ("BrainGate") in the near future. With the cooperation of a German company, active implants are being developed that are supposed to allow wireless transmission of signals, so the implanted subjects could be free of external wires and move around while they turn their thoughts into mechanical actions.

Another U.S. company (Neural Signals, Inc.), together with a research group from Atlanta, follows a "semi-invasive" strategy based on cone-shaped glass electrodes that are coated with biochemicals extracted from the patient's knees to stimulate nerve growth with gold wire electrode leads. These electrodes are placed on the surface of the brain, but neural processes (axons) can grow into the cones to form connections with the gold wires. This BCI has also been applied to patients who were able to control computer cursors by electrical brain activity generated during imagined movements (Friehs et al. 2004).

Medical indications for therapeutic application of a motor BMI include movement disorders, more specifically brain or spinal cord injury, cerebral palsy, stroke, and the degenerative disorders amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy - generally disorders, where patients have lost the ability to perform motor tasks due to loss of function either after brain lesions or lesions to spinal motor neurons (Friehs et al. 2004).

A brain-machine interface could help these patients - after a period of training - to move artificial limbs by thinking about moving them or even to regain (limited) control of there own muscles. The number of patients who might benefit from such a device is hard to estimate. Just for spinal cord injuries, there is a population of about 30,000 patients in Germany alone for whom a BMI could be a therapeutic option. This figure would translate into more than 100,000 patients in the United States. Market interests may soon become a factor that could propel research just as effectively as it has in cochlear implantation for the restoration of hearing.

Now that there are a number of reliable interfaces between neural tissue and electrodes in both clinical routine (see Chapter 4) and research, naturally there are also efforts to take up Delgado's early experiments from the 1960s and 1970s and to develop devices for electrical stimulation of very specific areas in the brain. While these experiments continue to cause public concern because of their potential for abuse (see discussion on ethical issues below), practical considerations come into play from very different directions:

Rats guided by electrical stimulation can already be made to run, climb, jump or turn left and right through microprobes the width of a hair, implanted in their brains. Stimuli are transmitted from a computer to the rat's brain via a radio receiver strapped to its back. One electrode stimulates the "feelgood" centre of the rat's brain, two other electrodes activate the cerebral regions which process signals from its left and right whiskers (Talwar et al. 2002). Those remote-controlled "robot rats" (Nicolelis 2002) could perhaps help to find earthquake victims.

3.3.4 Vagal Nerve Stimulation (VNS)

Compared to the latest anti-epileptic drugs, VNS therapy in epileptic patients has shown similar efficacy in clinical trials and the long-term results are even more positive, with continued improvement in seizure reduction for up to two years (Ben Menachem 2002; Ben Menachem and French 2005).

Still, VNS has not been generally accepted for use as a first line or even second line therapy because it is a surgical procedure. Moreover, the safety of MRI examinations, especially in 3Tesla scanners which may be needed in these patients in the course of the disease has not yet been established.

The side effects of VNS are totally different from those seen with antiepileptic medication. There have been no pharmacological interactions, cognitive or sedative side effects reported in any age group. Side effects are restricted to local irritation, hoarseness, coughing and, in a small number of patients, swallowing difficulties when the stimulator is on. The latter complication tends to disappear over time. Since stimulation is delivered automatically, patient compliance is guaranteed. The cost of the currently available "VNS Therapy System" (Cyberonics Inc.), when spread out over an average battery life of eight years, is reported to be less than the cost of using a new anti-epileptic drug over an eight-year period, and if frequent hospital stays due to seizures can be avoided, there might even be real cost savings with the system (Ben Menachem and French 2005).

With respect to the treatment of depression, Nemeroff et al. recently commented on the current situation in anti-depressant treatment:

Considerable strides have been made over the past 2 decades in the development of safe and efficacious antidepressants. Although truly novel therapies with mechanisms other than monoamine neurotransmitter reuptake inhibition represent an active area of investigation, they are years away from being clinically available. Unfortunately, up to 50% of patients with depression do not achieve remission with currently available treatments in short-term (i.e., 6-8 weeks), double-blind, clinical trials. (Nemeroff et al. 2006)

In this situation, new treatment methods were desperately needed for a disorder as common as depression. In Section 2.4 we have already sketched the rationale for including vagus nerve stimulation in the treatment plan. The first clinical trial, an acute (3-months period) open-label study with patients resistant to usual treatment, started at Baylor College (North Carolina, USA) in 1998, showed promising results (Rush et al. 2000; Nahas et al. 2005). A naturalistic follow-up study carried out by the same group with prolonged stimulation for one year confirmed these results, showing a (not statistically significant!) sustained response rate of 40% (12 of 30 patients) to 46% (13/28) and a significantly increased remission rate over the acute trial of 17% (5/30) to 29% (8/28). Moreover, significant improvements in func tion between acute study exit and the 1-year follow-up assessment as measured by the Medical Outcomes Study Short Form-36 were observed (Rush et al. 2005b).

Other studies, also combining VNS and treatment as usual (TAU), confirmed an improved long-term outcome of this combination over the usual treatment alone (George et al. 2005; Nahas et al. 2005). It was concluded that longer-term vagus nerve stimulation treatment was associated with sustained symptomatic benefit and sustained or enhanced functional status.

However, a 10-week acute, randomised, controlled, masked trial comparing adjunctive VNS with sham treatment in 235 outpatients with nonpsy-chotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25) at Baylor College failed to yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression. Effects of VNS + TAU were compared to Sham + TAU. In this study, medication was kept stable.

Response rates (>/=50% reduction from baseline) on a 24-item rating scale (Hamilton Rating Scale for Depression) were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) group. With a secondary outcome scale, based on self-report of the patients (Inventory of Depressive Symptomatology, IDS), response rates were 17.0% for active VNS and 7.3% for sham. VNS was well tolerated: Only 1% of the patients (3/235) left the study because of adverse events (Rush et al. 2005a). These ambiguous results show that there is a definite need for further research in this field - especially with respect to the mode and mechanisms of vagal nerve electrical stimulation.

At present, the delivery of VNS involves a surgical procedure that includes exposure of the carotid artery. Apart from cosmetic issues, MRI scanning options are restricted. In both epilepsy and depression, some patients will receive little to no benefit, despite having had surgery.

If ways were found to deliver VNS less invasively, or if it could be predicted which patients will benefit of the clinical applications, VNS would probably be used more widely. Preliminary attempts at stimulating the vagus nerve using a transcranial magnetic stimulator (TMS) have not been successful, partly because it the difficulty of finding reliable indicators to confirm that the TMS has activated the vagus (George et al. 2000). Another possibility might be to develop a temporary percutaneous method of stimulation (George et al. 2000) to test in advance whether a patient would benefit from an implant.

A PET study with epilepsy patients found that increased blood flow in the right and left thalamus during the initial VNS stimulation correlated with decreased seizures over the next few weeks (Henry 2002). This suggests that, if ways can be found for the transcutaneous stimulation of the vagus, functional imaging may help to select the patients most likely to benefit from this therapy.

It is also not clear yet if different fibre systems are involved in the different effects of VNS. Stimulation can be delivered at different amplitudes, frequencies and with different pulse widths, and at various duty cycles (ON/OFF time). It would appear that if stimulation parameters are varied from those commonly used for epilepsy (or depression), VNS might produce different CNS effects (George et al. 2000).

Apart from epilepsy and depression, ongoing research indicates that clinical indications may broaden in the future. Potential application of VNS for anxiety, cognitive enhancement in neurodegenerative diseases like Alzheimer's, migraines (Groves and Brown 2005), and the mediation of high blood pressure (Rosahl 2006) are currently under investigation.

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