brain research 1630 (2016) 208–224

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Review

Electrical stimulation of the brain and the development of cortical visual prostheses: An historical perspective Philip M. Lewisa,b,c,d, Jeffrey V. Rosenfelda,b,c,d,e,n a

Monash Vision Group, Department of Electrical and Computer Systems Engineering, Monash University, Wellington Road, Clayton, VIC 3800, Australia b Department of Neurosurgery, Level 1 Old Baker Building, Alfred Hospital, 55 Commercial Road, Melbourne, VIC 3004, Australia c Department of Surgery, Monash University Central Clinical School, Level 6 Alfred Centre, 99 Commercial Road, Melbourne, VIC 3004, Australia d Monash Institute of Medical Engineering, Monash University, Wellington Road, Clayton, VIC 3800, Australia e F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, United States

ar t ic l e in f o

abs tra ct

Article history:

Rapid advances are occurring in neural engineering, bionics and the brain–computer

Accepted 14 August 2015

interface. These milestones have been underpinned by staggering advances in micro-

Available online 5 September 2015

electronics, computing, and wireless technology in the last three decades. Several

Keywords:

cortically-based visual prosthetic devices are currently being developed, but pioneering

Bionics

advances with early implants were achieved by Brindley followed by Dobelle in the 1960s

Neural engineering

and 1970s. We have reviewed these discoveries within the historical context of the medical

Visual cortex

uses of electricity including attempts to cure blindness, the discovery of the visual cortex,

Blindness

and opportunities for cortex stimulation experiments during neurosurgery. Further

Electrodes

advances were made possible with improvements in electrode design, greater understanding of cortical electrophysiology and miniaturisation of electronic components. Human trials of a new generation of prototype cortical visual prostheses for the blind are imminent. This article is part of a Special Issue entitled Hold Item. & 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

n Correspondence to: Department of Neurosurgery, Level 1 Old Baker Building, Alfred Hospital, 55 Commercial Rd., Melbourne, VIC 3004, Australia. E-mail addresses: [email protected] (P.M. Lewis), [email protected] (J.V. Rosenfeld).

http://dx.doi.org/10.1016/j.brainres.2015.08.038 0006-8993/& 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Contents 1. 2. 3.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 The electrically excitable brain and occipital cortex as the primary visual centre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Visual cortical stimulation in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 3.1. The first “Bionic Vision” device . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 3.2. A multielectrode visual cortex stimulator implanted into a blind subject . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 3.3. Government and the scientific community respond . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 3.4. Further human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 3.5. Intracortical electrodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 4. High density electrode arrays for patterned stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 5. Wireless neurostimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 5.1. Early wireless brain stimulation experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 5.2. Wireless brain stimulators implanted into humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 5.3. Reducing the number of coils in high-electrode count wireless links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 6. Closing remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

1.

Introduction

2. The electrically excitable brain and occipital cortex as the primary visual centre

Advances in medicine, surgery and electronics have set the stage for a fusion of the physical and biological sciences; one in which prosthetic devices may restore lost functional capacity to the disabled. The emerging field of neuroprosthetics embodies the totality of this integration, whereby sensory (Carlson et al., 2012; Guenther et al., 2012; Weiland and Humayun, 2014), motor (Hochberg et al., 2012) and even cognitive (Hampson et al., 2012, 2013) deficits may be addressed. A significant share of the worldwide research effort in this regard is directed towards the development of visual prosthetics for the blind. Potential stimulation targets currently being investigated for visual prostheses include the retina (Chow et al., 2004; Dorn et al., 2013; Gerding et al., 2007; Stingl et al., 2013), optic nerve (Brelen et al., 2010; Sakaguchi et al., 2009; Wu et al., 2010), lateral geniculate body (Panetsos et al., 2011; Pezaris and Eskandar, 2009) and the cerebral cortex (Brindley and Lewin, 1968b; Dobelle, 2000; Schmidt et al., 1996). Human testing of implanted cortical electrode arrays for the evocation of visual percepts predates similar attempts at the retinal level by almost 30 years (Brindley and Lewin, 1968b; Humayun et al., 1996; Humayun et al., 1999). Moreover, visual cortical prostheses offering limited functionality were chronically implanted in a number of patients throughout the 1970s (Brindley, 1982; Dobelle et al., 1976; Dobelle et al., 1979). Two retinal devices recently obtained regulatory approval in Europe (Argus II and Alpha IMS), with the Argus II also having obtained regulatory approval in the US (Weiland and Humayun, 2014). Cortical devices remain experimental only. Imminent human trials of a new generation of improved cortical devices render it timely to review the history of their development, including early electrical stimulation of human cerebral cortex and the first pioneering attempts to restore visual sensation to a profoundly blind person over 50 years ago.

The literature on localisation of function in the brain and the discovery that the human brain is electrically excitable has been extensively reviewed, and will be given a relatively brief treatment here. For more detail, the reader is referred to the works of Gross (1998) and Finger (2001). The end of the 18th century saw the introduction of a electrophysiology as a scientific discipline, beginning with Galvani's 1791 discovery of the electrical excitability of nerves (Galvani and Aldini, 1791; Piccolino, 1997). Interestingly, Le Roy (1755) had unknowingly demonstrated the excitability of the eyes and/or optic nerves previously, reporting flashes of light seen by his patient, while receiving electric shocks to his patient's head as a treatment for blindness (Fig. 1). In 1800, Volta also noted that electrical stimulation of the eyes and/or optic nerves could induce the sensation of light, commenting that such stimulation may even be useful to reveal “paralysis of optic nerves” (Piccolino, 2000, p.151). This notion of electrical excitability was not extended to the cortex until some 80 years after Galvani's experiments on frog's legs. Indeed, despite the mounting evidence to the contrary, throughout the early 19th century there was a persistent belief that the cortex was inexcitable by electrical means (Carlson and Devinsky, 2009; Gross, 1998). Aldini's early 19th century demonstrations of muscular contractions in response to electrical stimulation of the exposed cortex were performed on deceased humans, thus offering little in the way of incontrovertible proof of cortical excitability. The dual questions of cortical functional localisation and electrical excitability were finally settled after the seminal work of Fritsch and Hitzig (1870) prompted further investigations by Ferrier (1874), (Munk, 1881a), Luciani and Tamburini (Rabagliati, 1879) and others (Gross, 2007). The combined works of these investigators provided conclusive evidence that not only did the cerebral cortex demonstrate functional topography, but this topography could be mapped precisely using electrical stimuli.

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experimental data, little was known about how the visual field was represented on the cortex. Munk proposed a pointto-point projection of the visual field to occipital cortex, suggesting that central vision was represented at its most posterior aspect (Fig. 2) (Munk, 1881a, 1881b, 1890). Notably, he ascribed a large area of occipital cortex to central vision, placing this area at the most posterior aspect of the occipital lobe (Munk, 1881b). Schäfer’s system of primate retinotopy largely agreed with Munk’s, and he placed central vision in “the mesial parts” of the occipital pole (Schäfer, 1888a). Insightfully, he noted that monkeys with bilateral mesial lesions quickly overcame their visual field defects, making the results of such studies difficult to interpret (Schäfer, 1888a): I believe, indeed, that to arrive at detailed conclusions we must await the results of perimetric observations in cases of cerebral lesion in the human subject (Schäfer, 1888a, p.6).

Fig. 1 – The apparatus constructed by Dr Charles Le Roy in his attempt to cure blindness with electrical stimulation. Reproduced from (Le Roy, 1755, p.98).

The 18th and 19th centuries also saw great advances in the understanding of cerebral anatomy. Gennari’s discovery of a thickened white layer within the posterior cortex (Glickstein and Rizzolatti, 1984), and the revealing of its connections to the eyes via the optic radiations, lateral thalamus and optic nerves suggested a role for occipital cortex in vision (Colombo et al., 2002; Rawlings and Rossitch, 1994; Simpson, 2005; Ture et al., 2000). By the mid19th century a body of functional and anatomical evidence had accumulated to support the existence of a discrete visual centre in the brain, which Panizza identified as occipital cortex (Colombo et al., 2002). Conclusive evidence in support of Panizza's claim, which was largely overlooked at the time (Colombo et al., 2002), was finally provided by the aforementioned research undertaken to resolve the issues of cortical localisation and electrical excitability. Ferrier initially denied that electrical stimulation of the occipital lobes in macaques could elicit any behavioural responses (e.g. eye movements), contending that the angular gyrus was the location of the visual centre (Ferrier, 1874). Ferrier’s claim was quickly refuted by Luciani and Tamburini, who declared the occipital lobes as “capable of reactions perfectly similar to those which arise on excitation of the angular gyrus, only less conspicuous” (Rabagliati, 1879, p.247). Schäfer and Horsley corroborated these findings, reporting regular eye movements produced in response “even to weak excitations” of the occipital lobes (Schäfer, 1888b, p.367). By the late 1880s there was sufficient evidence to support a primary role for the occipital lobe in canine and macaque vision (Brown and Schäfer, 1888; Colombo et al., 2002; Horsley and Schäfer, 1888; Rabagliati, 1879; Schäfer, 1888b). Despite this wealth of

After Henschen (1893) erroneously concluded that “the macular field may be more anterior, and the peripheral in the horizontal meridian, more posterior”, p. 178, Inouye (Glickstein and Whitteridge, 1987), Holmes and Lister (1916) and others (Chatelin, 1918; Riddoch, 1917) correctly mapped the retinotopy of visual cortex, having studied the visual field deficits of soldiers with occipital bullet wounds. These works culminated in Holmes' widely-cited retinocortical map published

Fig. 2 – Hermann Munk's illustration of the retinocortical projections in the dog. Reproduced from (Munk, 1881b, p.90).

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Fig. 3 – Retinotopic map of primary visual cortex derived from multiple studies on soldiers with occipital injuries. Reproduced from (Holmes, 1918) with permission from BMJ Publishing Group Ltd.

in 1918 (Fig. 3) (Holmes, 1918). They also served to corroborate the growing number of myeloarchitectonic studies including those of Flechsig (1901), Bolton (1900), Campbell (1905), Smith (1907) and Brodmann (1909) who delineated the boundaries of what became known as visuo-sensory cortex (Bolton, 1900), striate cortex (Smith, 1907) and eventually, primary visual cortex.

3.

Visual cortical stimulation in humans

Of the many late 19th century studies investigating the questions of cortical localisation and excitability, very few reports of experiments on human subjects were published. Hitzig described eye movements in response to posterior cortical stimulation on human subjects (Fritsch and Hitzig, 1870), however a more detailed report, which was ultimately decried on ethical grounds (Harris and Almerigi, 2009), was published four years later by Bartholow (1874). Similar cases of direct cortical stimulation in humans were subsequently reported in 1882 and 1883 by Sciamanna and Alberti respectively (Zago et al., 2008). All three cases served to illustrate the validity of Fritsch and Hitzig's findings of cortical excitability in humans, however did not contribute to the literature on the functions of visual cortex or visual cortical stimulation. Horsley (1884) reported on the case of a 6-week old child with an occipital encephalocele that he electrically stimulated. Horsley described rapid conjugate deviations of the child's eyes upon stimulation of the herniated brain, which included the tips of the occipital lobes. Horsley made no inferences about the role of occipital cortex from this observation, concluding that the eye movements were in response to stimulation of the quadrigeminal bodies.

The year Holmes published his retinocortical map, Löwenstein and Borchardt published the results of occipital electrical stimulation performed in a patient who had presented three years earlier with persistent seizures and narrowing of his visual field (Löwenstein and Borchardt, 1918). The patient had received a bullet wound to the left side of his head which produced an epileptogenic lesion. After exposing the wound and removing two fragments of bone the size of a fingernail from the patient's brain, Borchardt stimulated the exposed cortex. The patient reported seeing a flickering light in his right visual field, closely resembling the hallucinations preceding the onset of his seizures. Thus it was shown that electrical stimulation of human visual cortex could produce the sensation of point sources of light. In 1928, six years after the work of Löwenstein and Borchardt, Krause reported in more detail on the results of cortical electrical stimulation (or Faradization, as it was still being called) on yet another gunshot victim. This man also presented with persistent seizures preceded by visual phenomena, suggesting an occipital focus (Krause, 1924; Krause and Schum, 1931). After draining an occipital cyst, Krause stimulated the cortex around the rim of the entrance to the cyst cavity. Krause's patient reported seeing expanding, jagged rings of light and stars, either arranged in rings, clustered or individually. Krause did not provide a detailed description of the stimulus strength, other than to state that it was sufficient to cause tingling and then stinging on his moistened fingertips after increasing the strength, and that no seizures occurred as a result of stimulation. Krause made an important observation during these experiments that would have significance for future attempts to stimulate the visual cortex in the blind. He observed that his patient, who had been hemianopic for some nine years, still experienced visual hallucinations in his blind hemifield prior to the onset of a seizure. Moreover,

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electrical stimulation could evoke similar visual perceptions in the blind hemifield (Krause, 1924). In 1929, Förster reported on an even more detailed examination of another patient with a projectile injury resulting in occipital seizures (Förster, 1929). Förster, a pioneering neurologist and self-taught neurosurgeon who did extensive electrical stimulation experiments for cortical mapping during surgery for epilepsy (Piotrowska and Winkler, 2007), expanded on Krause's observations in two ways: firstly he demonstrated that stimulation of the occipital pole and its surrounding cortex produced phosphenes that remained motionless and were localised to the centre of the patient’s visual field; secondly, that stimulation striate cortex anteriorly produced phosphenes in the periphery, confirming the general topology of the retinocortical map put forward by Inouye and Holmes. Penfield, who was a student of Förster (Piotrowska and Winkler, 2007), also reported on the results of 17 years of visual cortex stimulation, performed in some 330 operations (Penfield, 1947). Penfield stimulated quite a wide area of cortex in total, including one point well outside the occipital lobe, which paradoxically still produced visual imagery. The observations of Penfield concurred with those of his predecessors, with the notable addition that his patients described seeing spots or shapes of specific colours, including”yellow, pink, blue, red, green, fiery, grey, fawn” (Penfield, 1947, p.340). By the 1950s, it was well known that electrical stimulation of the occipital poles could produce punctate phosphenes in the centre of the visual field. This knowledge, plus Krause's observation that it was possible for a blind patient to perceive visual imagery upon stimulation of the occipital cortex, prompted the suggestion by Krieg in 1953 that a visual prosthesis might be a practical possibility (Ronner et al., 1980). A method for performing such stimulation to aid the blind was subsequently patented in 1955 by Shaw (1955). The first real attempt to perform visual cortical stimulation expressly for the purposes of restoring lost visual perception to a blind person took place 39 years after Löwenstein and Borchardt's (1918) paper.

3.1.

media coverage (Shipley, 1959), Button did not publish his results in the general scientific literature until 1962, and even then in a journal little-known to the wider scientific community (Button and Putnam, 1962). Button and Putnam's first patient was a 36-year old woman with an 18-year history of total blindness, having lost her sight following surgery for an occipital tuberculoma. Two pairs of stainless steel wires, approximately 76 mm in diameter and insulated to within 1 mm of their tips, were implanted through burr-holes either side of the inion into the cortex at depths of 1.5, 3, 5, and 7 cm (Button and Putnam, 1962). These were then connected to a simple visual cortical stimulator (Fig. 4), the parts for which were reportedly purchased at a second-hand electronics dealer for the sum of US$9.45 (Button, 1958).The patient reported seeing flashes of light, most vividly and with no accompanying discomfort when a 75-Hz, 620-mA stimulus was applied. With a lightdetecting “photocell” attached to the stimulating circuitry, the patient was able to detect the presence and relative brightness of a light source, describing the sensation of stimulus as “somewhat as the sun might appear to a sighted person through closed eyelids” (Button and Putnam, 1962, p.18). Button and Putnam demonstrated the limited practical utility of such a simple device by moving a 40-watt light bulb around a darkened room, while instructing the patient to locate it. She reportedly did this repeatedly and with little practice required. In their second series of experiments and using a modified stimulating apparatus, Button and Putnam were able to evoke coloured phosphenes (red and white) in one patient, as Penfield had done before them (Penfield, 1947). They also reported visual perception, albeit of a more complex nature, in a 32-year old patient who had been blind since the age of 5 and had no memory of vision (Button and Putnam, 1962). Despite their obvious successes and Button’s plans to implant “not four, but several hundred” (Button, 1958, p.55) electrodes, Button and Putnam did not continue their experiments beyond the second series. The journalist Donald Oakley, having worked with Button in 1964 on a news article

The first “Bionic Vision” device

I See a Flash! (Button, 1958, p.54) In 1957, John C. Button, Jr. was a busy osteopath who had an interest in neurology, in particular, the potential offered by electronics for the restoration of lost sensory function (Oakley, 2011b). Determined to test the utility of electrical stimulation for generating useful visual stimuli in the blind, Button convinced Tracey Putnam, then Chief of Neurosurgery at Cedars of Lebanon Hospital (now Cedars-Sinai) in Los Angeles, to collaborate and help him realise his ideas. The outcome of their collaboration was a successful, but ultimately discontinued series of experiments demonstrating a simple device to evoke sensations of light in the blind (Button and Putnam, 1962; Button, 1958). Their work received brief but intense media attention, including an article on the front page of the New York Times in November of 1957 with the headline “Woman, Blind 18 Years, ‘Sees’ by Photocell and Wires in Brain” (Plumb, 1957). Curiously, despite presenting at an engineering conference just prior to the work receiving

Fig. 4 – Photograph of the stimulating apparatus devised by John C. Button, which was connected to an array of four stainless steel wires implanted in the occipital cortex of a blind woman. Reprinted with permission from RadioElectronics Magazine, December 1958 (Button, 1958).

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about his visual cortex stimulation experiments (Oakley, 2011a; Oakley, 2011b), offers some possible explanations. Inability to obtain sufficient funding, which Button attributed in part to his lack of a “credible” medical qualification, was reportedly to blame for the sudden discontinuation of their work (Oakley, 2011a). Oakley also referred to the negative commentary on the prospects for “corticogenic vision” offered by Shipley (1959), who questioned whether a sufficient number of discrete phosphenes could be elicited to provide useful vision. Shipley summed up by stating that “Work in this area should be undertaken with great restraint and extreme scientific caution” (Shipley, 1959, p.362). Thus it was in a climate of “passive indifference (and even occasional active hostility)” (Sterling, 1971, p.xv) towards the concept of visual prosthetics, that a conference on the topic was held in Endicott House at the Massachusetts Institute of Technology, in 1966. The conference chair Theodore Sterling explained that after initial difficulty in bringing together potential participants, the conference was finally held under the proviso that the proceedings would not be made publicly accessible (Sterling 1971a). Sterling also wrote that the conference “made it openly possible for work on a visual prosthesis to begin” (Sterling, 1971, p.xvii) and “made possible such actions as the release of some seed money by the National Institute of Neurological Diseases and Blindness for the support of a few exploratory planning studies” (Sterling, 1971, p.xvii). The NIH implemented a coordinated neuroprosthetics programme at the US National Institute of Neurological Diseases and Blindness (NINDB) the following year. In his first annual report to the NIH, Karl Frank, chief of the laboratory, wrote prophetically about the role his team had to play (National Institute of Neurological Diseases and Blindness, 1968): The future development of mankind may depend to a significant extent on the development of techniques for neural control. It is important, therefore, to know what possibilities exist for direct connection of the nervous system to the outside world (National Institute of Neurological Diseases and Blindness, 1968, p.4o). Clearly, there was a growing interest at both a governmental level and within the scientific community for the concept of neural prosthetics and electrical stimulation for visual prostheses in particular. Therefore, when Brindley and Lewin published a report just two years later on the successful human implantation and testing of a multielectrode visual cortex stimulator, it garnered significant and widespread attention (Sterling, 1971).

3.2. A multielectrode visual cortex stimulator implanted into a blind subject Throughout the mid 1960s Giles Brindley, a physiologist at the University of Cambridge, had been undertaking a programme of research to support the development of a fully implanted, multielectrode wireless visual cortex stimulation device (Brindley, 1965a; Brindley, 1965b). One of Brindley's goals was to enable the reading of printed or handwritten text by prosthesis recipients; he therefore examined the minimum number of light points or “information channels” required to achieve this goal, coming to the conclusion that 50 channels

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should permit reading 10 letters at a time if the reader was presented with a modified alphabet (Brindley, 1965a), or a single letter of handwritten or typed text (Brindley and Lewin, 1968b). He also recognised that the ability to read with so few points available for pattern generation would depend largely on the “favourable” positioning of phosphenes within the visual field. To enable reading at normal speeds when presented with handwritten or typed text it was determined that 600 channels would be required, far more than could managed at that time (Brindley, 1965a). Brindley expected that his implants would remain in situ for lengthy periods, thus direct electrical connection to the electrodes and its inherent infection risk due to skin penetration was unacceptable and the system was designed from the outset to be wirelessly operated. However, acknowledging the sheer number of electrodes to be stimulated and the resultant likely physical bulk of the data receiving electronics, he made improvements to allow for a more condensed array of coils that would also continue to permit selective stimulation of electrodes (Brindley, 1965b). Finally, the long-term viability of the implant was established in baboons prior to the first human testing, demonstrating that despite fibrous encapsulation of the electrodes, the electrical integrity of the electrode/tissue interface was not grossly impaired even after two years of implantation (Brindley and Lewin, 1968b). Brindley and Lewin performed their first human implantation in July 1967, publishing their experiences in the Journal of Physiology the following year (Brindley and Lewin, 1968a, 1968b). The final implant, which was highly sophisticated for the time, consisted of an array of 80 small (0.64 mm2), square platinum surface electrodes embedded in a silicone cap, moulded to fit one occipital cortex of the patient (Fig. 5b). Each electrode was hard-wired to one of an array of receiving coils that were also encapsulated in silicone and implanted under the scalp. The stimulation of an individual electrode was achieved by placing a transmitting coil directly over a matched receiving coil that was tuned to the same frequency. The transmitted signal was then converted into electrode stimulus pulses by simple circuitry contained within the receiving coils (Fig. 5a). Thirty-nine electrodes in the implant generated phosphenes over a large area of the patient's visual field (Fig. 5c). Brindley mapped the phosphenes using a “bowl perimeter”, which had a centrally-located knob for the patient to grasp. Holding the knob with one hand and maintaining gaze at this central point, the patient pointed to the phosphenes with the other hand, allowing Brindley to build up a map of their location and size. Centrally evoked phosphenes were described as a small, flickering “grain of sago at arm's length” (Brindley and Lewin, 1968b, p.483) whereas those in the periphery became more variable in size, brightness, shape and sharpness. The relationship between electrode position and phosphene location was described as “roughly concordant” with previously published retinocortical maps (Glickstein and Whitteridge, 1987; Holmes, 1918). The lack of phosphenes elicited in the lateral visual field was expected, given the understanding that visual cortex subserving this region was buried inside the calcarine fissure. However for selected electrodes, suprathreshold stimulation produced an additional conjugate phosphene

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Fig. 5 – a: Brindley stimulating the visual cortex of his first implant recipient, placing a stmulating coil over a matched receiving coil implanted under her scalp. 5b: Plain X-Ray showing the placement of electrode arrays on the implant recipient's visual cortex and receiving coils under the scalp. 5c: Visual field map of phosphenes generated by the implant. Numbers refer to the electrode being stimulated. Note that some phosphenes are elongated, and some multiple (with curly braces) phosphenes appear when a single electrode is stimulated. 5a is reproduced from the personal collection of Prof G.S. Brindley, with permission. Figures 5b,c reproduced from (Brindley and Lewin, 1968b), with permission from John Wiley and Sons.

inverted about the horizontal meridian. Other electrodes produced clusters of phosphenes which did not resolve to a single percept when stimulus intensity was reduced. When selected closely-spaced (2.4 mm) electrodes were synchronously stimulated, the resulting discrete phosphenes fused into a diffuse strip of light. For the remainder, phosphenes remained discriminable when adjacent pairs were synchronously stimulated. Phosphene brightness was influenced by stimulus pulse width intensity, however stimulation at 1.5x threshold or greater could result in phosphenes that did not extinguish at stimulus cessation. Overall, the irregular distribution of phosphenes made the generation of useful patterns such as letters of the alphabet difficult, although the patient was reportedly able to recognise the letters L, V and a question mark (Brindley, 1971). Thus, while the end result was a device of little practical utility to the recipient, Brindley was confident that by increasing the density of electrodes within the accessible area of visual cortex, the original goals of reading and even obstacle avoidance while walking may ultimately be met (Brindley and Lewin, 1968b).

3.3.

one of which was based on an electrode array comprising 4000–10,000 electrodes spread across both visual cortices, receiving input from a small forehead-mounted camera. The authors described “serious problems” encountered in the fabrication of such a densely-packed array of electrodes (Schimmel and Vaughan, 1971; Vaughan and Schimmel, 1970). Moreover, Vaughan expressed general concerns about the cost of developing devices such as those proposed by Marg (1971), which in his opinion, would require “sums of money which are in the order of magnitude of the entire present expenditure for research and development in the area of blindness” (Marg, 1971, p.247). The year after the 2nd Conference on Visual Prosthesis the NINDB, now renamed the National Institute for Neurological Diseases and Stroke (NINDS), funded a number of projects in pursuit of establishing the viability of a sensory prosthesis for the blind (Hambrecht and Frank, 1975; National Institute of Neurological Diseases and Blindness, 1971; Pollen, 1975). Through this additional funding and the ongoing efforts of other groups already working in the field, there was a steady increase in the development of neuroprosthetic and specifically visual prosthetic technologies throughout the 1970s.

Government and the scientific community respond 3.4.

The same year Brindley and Lewin published their groundbreaking paper, the UK Medical Research Council formed the Neurological Prosthesis Unit, with Brindley as its director (Donaldson, 1987). Across the Atlantic, the scientific community in the United States was also reacting. Such was the interest in Brindley and Lewin's work that a second Conference on Visual Prosthesis was convened, taking place in June 1969 (Sterling, 1971). Papers on a wide range of topics relevant to visual prosthetics were presented and discussed, including vision substitution, retinal and deep-brain stimulation, and the role of image processing in generating useful phosphene-based imagery (Sterling and Weinkam, 1971). Detailed designs for cortical visual prostheses were presented by two groups (Marg, 1971; Schimmel and Vaughan, 1971),

Further human studies

At the Neurological Prosthesis Unit in the United Kingdom, Brindley and his engineering colleagues continued their visual prosthesis development and testing programme. Brindley and Donaldson improved on Brindley’s original implant design (Brindley, 1970; Brindley, 1971; Donaldson, 1973), implanting their improved device into a 64-year old man with retinitis pigmentosa in 1972 (Brindley et al., 1972). Improvements included bilateral electrode arrays and a system of electrode addressing, allowing each receiving coil to stimulate several electrodes (Brindley, 1970; Donaldson, 1973). The second implant produced up to 68 phosphenes (Brindley et al., 1972), which were larger, overlapping and often fused into a single percept when closely-spaced

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electrodes were stimulated. Nonetheless, the patient was able to discriminate between overlapping phosphenes upon sequential stimulation. Subsequently, six electrodes producing phosphenes forming an approximate 3  2 grid, were stimulated by a device that electrically translated English letterforms from a paper tape reader into Braille characters. The patient was able to read Braille characters constructed from these phosphenes at a rate of 7 letters per minute with 90% accuracy (Donaldson, 1973). Continued testing on the same patient demonstrated that stimulation of a single electrode could influence the responses of electrodes within a 5 mm radius due to spread of stimulation current (Brindley and Rushton, 1974). For example, it was reported that subthreshold stimulation of one electrode would lower the stimulus threshold for another if the two were synchronously stimulated and separated by less than 5 mm. Moreover, synchronous stimulation also influenced the relative brightness of phosphenes produced by closely-spaced electrodes, whereas asynchronous stimuli eliminated such interactions (Brindley and Rushton, 1974). Brindley remained determined to pursue the goal of reading conventional letterforms (Brindley, 1982), and his group continued developing improved implants into the 1980s including one with 151 electrodes (Fig. 6) (Brindley, 1982). This device unfortunately became infected and had to be removed (Rushton et al., 1989). Brindley’s research eventually diversified into more widespread applications of neurostimulation, and the UK Neurological Prosthesis Unit reported no further visual cortical prosthesis implants after 1982. In 1968 the University of Utah instigated a sensory prosthesis research programme under Willem J. Kolff, with William Dobelle as programme director (Dobelle, 1998). Continuing with support from the National Institutes of Health (NIH) (Hambrecht and Frank, 1975; National Institute of Neurological Diseases and Blindness, 1971; Pollen, 1975), Dobelle made rapid progress on developing a cortical visual prosthesis. Dobelle worked with the Huntington Institute for Applied Medical Research to develop a removable multielectrode cortical surface array, which was tested on 36 sighted patients undergoing occipital surgery (Dobelle and Mladejovsky, 1974; Klomp et al., 1977; National Institute of

Fig. 6 – “Miss Bonnett”, recipient of the last visual cortex implant built by the MRC Neurological Prostheses Unit. Miss Bonnett is seen wearing an array of stimulating coils overlying her scalp, under which the receiving coils are implanted. The implant was removed after one year due to infection. Image from the MRC Neurological Prostheses Unit collection, with permission.

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Neurological Diseases and Blindness, 1971). Their final array design was quite different to Brindley's; it was a flat ribbonstyle array, manufactured out of Teflon, and placed only over the mesial occipital cortex, rather than cupping the occipital pole (Dobelle and Mladejovsky, 1974). The arrays contained 64 hexagonally arranged platinum discs, each of 1-mm2 surface area (Dobelle et al., 1974; Klomp et al., 1977). Their initial testing gave results that were in general agreement with those of Brindley and Lewin with several exceptions: Phosphenes did not always flicker and were occasionally coloured, always disappeared immediately upon cessation of stimulus, and gradually faded with continuous pulse trains. Moreover, in these sighted volunteers, phosphenes could only be evoked from stimulation of primary visual cortex, whereas Brindley’s first two blind patients reported phosphenes also from stimulation of V2, or Brodmann area 18 (Brindley and Lewin, 1968b; Brindley et al., 1972). Additionally, Dobelle and Mladejovsky reported no persistence of phosphenes, although they attributed this to their use of lower stimulation currents (Dobelle and Mladejovsky, 1974). Dobelle's group then progressed to studies in blind volunteers, working with Canadian neurosurgeon John P. Girvin to implant electrode arrays into two subjects, the first of whom had been blind for 28 years, the other for 7 years (Dobelle et al., 1974). Their findings in blind subjects were in closer agreement with Brindley's, including the observation of phosphene persistence with suprathreshold stimulation, and that phosphenes could be elicited with stimulation of V2. However, in contrast to Brindley and Lewin (Brindley and Lewin, 1968b), and consistent with their own previous studies on sighted volunteers (Dobelle and Mladejovsky, 1974), Dobelle et al again found that continuous stimulation caused a diminution of phosphene brightness after 10–15 s (Dobelle et al., 1974). Adding further support to the notion of differential stimulation effects in the long-term blind, the subject blind for 28 years reported uniformly sized, consistently flickering phosphenes, which were elicited by stimulation of electrodes overlying both primary and secondary visual cortices. Conversely, the subject blind for 7 years reported both stable and flickering phosphenes of a radius that increased with distance from the centre of the visual field, as observed by Brindley's first patient who herself had been blind for only 4 years prior to receiving an implant (Brindley and Lewin, 1968a). Another group funded by the NIH and based at the Massachusetts General Hospital in Boston undertook intraoperative visual cortex stimulation studies with single surface electrodes throughout the early 1970s. They stimulated the visual cortex of five patients undergoing occipital craniotomies for tumour excision or cortical mapping for epilepsy. Of these, only three patients reported seeing phosphenes, with the two failures attributed to postoperative swelling and patient drowsiness (Pollen, 1975). In their report, Pollen et al. described the results of stimulation as being largely in agreement with those of the UK and Utah groups. One interesting point of difference was that they found it was possible to elicit smaller phosphenes and at lower currents by stimulating with the smallest electrodes (0.25-mm diameter). This contrasted with Dobelle's findings that altering electrode size did not substantially alter stimulus thresholds or the

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perception of phosphenes (Dobelle and Mladejovsky, 1974). The authors also described a relationship between the latency of phosphene on/off perception and stimulus current, suggesting a possible current-dependent limitation on the maximum rate of phosphene presentation and extinction. Despite this limitation, the authors concluded that the phosphene perception times were still “fast enough for rapid information transfer” (Pollen, 1975, p.524). Interactions between paired stimulating electrodes were seen with interelectrode spacings of 5 mm, with a separation of 8 mm required before subjects could discriminate phosphenes. The same group also conducted studies investigating the patterns of neural firing resulting from visual cortex stimulation in cats (Pollen, 1977). The authors examined the relationship between stimulus parameters and the development of neuronal afterdischarges, the prevention of which was a key requirement for ensuring that the risk of seizures and cortical kindling was minimised (Goddard et al., 1969). Moreover, phosphene persistence, which was observed in Brindley and Dobelle's blind patients (Brindley and Lewin, 1968b; Dobelle et al., 1974) and believed to be the result of neuronal afterdischarges, would limit the ability of a visual implant to convey rapidly changing information (Dobelle and Mladejovsky, 1974). Pollen et al found that shorter stimulus trains (o2 s) markedly increased the maximum stimulus current that could be delivered before neuronal afterdischarges were produced (Pollen, 1977). Additionally, administration of phenytoin at doses of 5 mg/kg produced a threefold increase in the neuronal afterdischarge current threshold, although the authors could not comment on whether the perception of phosphenes at a given stimulus current would be altered by the drug. Spread of current via surface stimulation was also found to influence the activity of neurons within 1.5–2 mm of the stimulating electrode which, unlike the group’s previous observations in human volunteers (Pollen, 1975), was consistent with previous observations (Brindley and Lewin, 1968b; Dobelle et al., 1974) of discriminable phosphenes elicited by stimulation of electrodes separated by 2–3 mm. The authors pointedly commented that this current spread was “the single greatest drawback to the design of a really useful prosthesis based upon stimulation with surface electrodes” (Pollen, 1977, p.84). Over the same period, researchers from the Huntington Institute of Applied Medical Research also developed and tested a cortical array of their own design (Pudenz, 1993; Talalla et al., 1974). The group was headed by Robert Pudenz, a previous student of Penfield and a founding member of the Institute (The Society of Neurological Surgeons, 2012). Their system comprised smaller, “strip” arrays of 18 platinum surface electrodes, placed separately on both the occipital pole and mesial occipital cortex of normally sighted patients. These patients also underwent occipital craniotomies, one subsequent to a gunshot wound to the head, with the remainder for subdural haematomas (Pudenz, 1993). During stimulation, the patients saw phosphenes of a size, colour and in locations consistent with previous observations on sighted subjects or those who had lost their sight relatively recently. Notably, unlike with Brindley and Dobelle's experiments, the authors were unable to elicit multiple phosphenes (Talalla et al., 1974). The group's tests also exposed a

significant risk associated with cortical stimulation: seizures. In a 1993 lecture on the group's experiences with the cortical visual prosthesis project in the 1970s, Pudenz described how one patient experienced two convulsive seizures and a transient left homonymous hemianopia, with the first seizure commencing one hour after stimulation (Pudenz, 1993). With another patient complaining of severe frontal pain during stimulation sessions, a review of these complications with the NIH, who funded the work, resulted in the cessation of the group's programme of developing a visual prosthesis in favour of research focussing on “safe and effective methods for neural stimulation” (Pudenz, 1993, p.238). Dobelle and colleagues continued to develop their implant throughout the 1970s, incorporating a transcutaneous connector (Dobelle et al., 1976) to permit chronic implantation of electrodes that had previously only been temporarily implanted (Dobelle et al., 1974). The stimulating hardware could therefore be readily detached and reattached allowing for more extensive testing, and their next patient was subsequently able, with reportedly little training, to read “cortical Braille” characters noticeably faster and with greater accuracy than using the tactile method (Dobelle et al., 1976). One of Dobelle’s early patients retained his implant for over 20 years, with no reported complications of infection or seizure. Moreover, his implant remained functional, allowing for enhancements via upgraded image processing software and hardware including miniaturised, spectacles-mounted cameras (Dobelle, 2000). (Fig. 7) Such enhancements significantly improved the functionality of the device, eventually allowing the recipient to navigate around a room of mannequins, retrieve objects, count fingers and even read letters on a Snellen chart. This case earned Dobelle and his patient an entry in the Guinness Book of World Records for the “First Successful Artificial Eye” (D'Antona et al., 1995). By 2002, continued development of the supporting technology enabled a new implant recipient to drive a car, with the upgrades permitting more effective recognition of obstacles in particular (Kotler, 2002). This same recipient later published a memoir describing his experiences with the Dobelle implant, in which he detailed complications including seizures suffered during threshold testing, wound

Fig. 7 – A recipient of the Dobelle implant, first implanted in 1978. In 2000 his external hardware and software was upgraded, including the miniature glasses-mounted camera shown, greatly enhancing the functionality of his prosthesis. Reproduced from (Dobelle, 2000), with permission.

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breakdown around the transcutaneous connector and ultimately complete failure of the device (Naumann, 2012). The year after this patient was implanted, Dobelle was conominated along with W.J. Kolff for the 2003 Nobel Prize in Medicine and Physiology (Oakley, 2011b). The following year Dobelle passed away from complications of diabetes. At the behest of his family, the visual prosthesis intellectual property was transferred to Stonybrook University in the state of New York, USA, with research currently ongoing within the university's Department of Biomedical Engineering (Lin, 2006; Naumann, 2012).

3.5.

Intracortical electrodes

While early human studies (o1960s) of cortical stimulation tended to avoid penetrating and therefore damaging the cortex, there are scattered reports of human brain stimulation experiments involving intracortical electrodes (Bartholow, 1874; Penfield, 1947). Button and Putnam described using very thin (76 mm) stainless steel wires implanted in the occipital cortex, with reportedly no complications (Button and Putnam, 1962; Button, 1958). The advantages of intracortical electrodes were not immediately evident in Button and Putnam’s results. Button stated in 1958 that “the keenest flashes of light” (Button, 1958, p. 54), which largely consisted of phosphenes filling much of the patient’s visual field, were obtained with stimulus currents of 620 mA. Conversely, Doty demonstrated in 1965 that stimulation of intracortical electrodes at currents as low as 50 mA could be detected by trained macaques, who would respond by pressing a lever (Doty, 1965). Moreover, it was shown that the locations of visual phenomena produced by stimulation with electrodes spaced as closely as 1-mm apart could be discriminated with a high degree of accuracy (Doty, 1965), undoubtedly due to the much smaller population of neurons being stimulated (Stoney et al., 1968). Nevertheless, a feature common to human visual prosthesis research in the two decades after Button and Putnam was the use of surface stimulating electrodes, which require currents in the order of 0.5–3 mA to generate phosphenes. The magnitude of current required in these early studies using surface stimulation was also thought to be responsible for the production of multiple phosphenes, a problem that Klomp and Dobelle attempted to address by adding a ground plane to their array. This ran between the electrodes, providing a return path close to the electrodes being stimulated (Dobelle, 2000; Klomp et al., 1977). By 1980, ongoing research had refined the lower limit of stimulus threshold current for intracortical stimulation, which was shown to be as low as 2 mA at certain points in the visual cortex of macaques (Bartlett and Doty, 1980). Moreover, these lowest thresholds were obtained at penetration depths consistent with layers V/VI of V1 (Bartlett and Doty, 1980). Other studies had suggested that, while electrical degradation of intracortical electrodes may cause a rise in stimulus threshold, lengthy periods of stimulation were a practical possibility, particularly if electrodes were made from iridium (Bartlett et al., 1977; White and Gross, 1974). Despite these promising results in animals, early human trials of visual cortical stimulation with intracortical electrodes were nonetheless generally unsuccessful (Dobelle and Mladejovsky, 1974; Hitchcock, 1982).

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In 1982 a Russian group successfully produced phosphenes by stimulation with 200-mm diameter platinum penetrating electrodes, inserted in bundles of 2–3 into the occipital pole of patients undergoing tumour surgery (Shakhnovich et al., 1982). The lower threshold for phosphene generation was reported as 4 V, however, currents were not quoted. The next report of intracortical electrodes stimulating human visual cortex came 8 years later, from researchers at the NINDS working with Dobelle's previous collaborator John Girvin, and a biomedical engineer from Queen's University in Kingston, Ontario (Bak et al., 1990). The group had been developing and testing intracortical electrodes since the 1970s (Loeb et al., 1977; Salcman and Bak, 1973; Salcman and Bak, 1976), and they had successfully demonstrated single-unit neural recording in primates over periods of up to 3 years (Schmidt et al., 1976; Schmidt et al., 1988). The group implanted sharpened iridium electrodes that were approximately 3-mm long and 37.5 mm in diameter into the occipital cortex of three epileptic patients undergoing occipital craniotomies. Using biphasic stimulus pulses delivered at 100 Hz, the group successfully elicited phosphenes from intracortical electrodes at thresholds were that were substantially lower than with surface electrodes. The lowest threshold (20 mA) was recorded at a depth of 2–3 mm in one subject, while in the other two subjects the lowest thresholds (80 mA and 200 mA) were obtained at 4 mm and 5 mm respectively, from the cortical surface (Bak et al., 1990). The authors also varied the interelectrode spacing, with discriminable phosphenes obtained from some electrodes spaced only 0.5mm apart. Thus it was suggested that a human cortical implant based on penetrating electrodes could potentially offer a substantial resolution increase over previous devices. Six years later, the same group implanted 38 of the same microelectrodes into the visual cortex of a volunteer who had been blind for 22 years (Schmidt et al., 1996). Reporting no visual phenomena from cortical surface electrode stimulation, the volunteer was able to perceive phosphenes from intracortical stimulation at currents as low as 1.9 mA. Moreover, no phosphenes flickered, and general characteristics such as brightness and size were controllable just as in previous studies. Coloured phosphenes were elicited by stimulation with near-threshold currents; with increasing current, these tended to become light yellow, light grey or white. The testing also reproduced the gradual diminution or “accommodation” of phosphene brightness first reported by Dobelle's group using surface electrodes (Dobelle and Mladejovsky, 1974; Dobelle et al., 1974), which could complicate the presentation of phosphenes of a consistent brightness (Schmidt et al., 1996). The previously-reported (Brindley and Lewin, 1968b; Dobelle et al., 1974) phenomenon of additional phosphenes elicited by suprathreshold stimulation of single electrodes was also reproduced, however in this case Schmidt et al were able to eliminate the extra phosphenes by reducing stimulus current. The authors hypothesised that the additional phosphenes may have resulted from current spread and therefore stimulation of adjacent cortical columns or in the case of the conjugate phosphenes, spread of current to adjacent cortical gyri (Schmidt et al., 1996). This series of experiments constituted a significant step forwards in cortical visual prosthesis research, demonstrating that

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intracortical electrodes could produce stable, punctate phosphenes in people with longstanding blindness. Moreover, these phosphenes could be elicited at stimulation currents several orders of magnitude lower than those required with surface electrodes, limiting the spread of stimulation current and permitting a five-fold reduction in electrode spacing while retaining two-point discriminability of phosphenes (Schmidt et al., 1996). Unfortunately, electrode failures limited the group's ability to explore shape recognition during stimulation of multiple electrodes. Moreover, Brindley (Brindley, 1965a) and Cha et al. (1992a, 1992b) had previously determined that several hundred or more phosphenes would be required to permit reading or ambulation. Schmidt et al implanted 39 electrodes, of which a maximum of 6 were concurrently stimulated to produce a vertical line (Schmidt et al., 1996). It therefore remained unknown whether stimulation of the large numbers of electrodes required for a functional prosthesis was safe, or indeed whether it would result in the numbers of discrete phosphenes that would be required to generate complex patterns that could be recognised by the recipient.

4. High density electrode arrays for patterned stimulation The studies undertaken at the NINDS by Bak and Schmidt used electrodes that were assembled from individual wires, bonded together by small blobs of epoxy resin (Bak et al., 1990; Schmidt et al., 1996). In the late 1980s and early 1990s, researchers at the Universities of Utah and Michigan were developing methods for producing larger arrays of densely packed electrodes for intracortical stimulation and recording (Hoogerwerf and Wise, 1991, 1994; Jones et al., 1992; Normann et al., 1989). The Utah group machined and etched electrodes from a block of silicon, with glass added at the base to provide an insulating layer between each shank. The array contained 100 sharpened electrodes with tips spaced approximately 400-mm apart, for a final array size of approximately 16 mm2 (Fig. 8). While not originally designed for the purpose of building a visual prosthesis, the “Utah Electrode Array” or UEA as it became known, was identified as a candidate device

Fig. 8 – Scanning electron micrograph of the Utah electrode array. At the top of the image is a scale bar, illustrating its small size. Reproduced from (Normann et al., 1999), with permission from Elsevier.

for enabling such research after the encouraging results of Bak and Schmidt (Normann et al., 1999). The Utah array has been further developed for a motor neuroprosthesis, enabling recording of neural activity over a 5-year period, and control of a robotic arm by a tetraplegic volunteer (Hochberg et al., 2012). The Michigan group utilised existing lithographic silicon fabrication technology to produce planar multiprobe arrays for neural recording. These planar arrays were subsequently stacked to produce a two-dimensional multielectrode array with probe spacings of between 100–200 mm (Hoogerwerf and Wise, 1991, 1994). Their first array was a 4  4 electrode device, connected by ribbon cable to a larger bonding pad that allowed for chronic intracortical implantation. Later iterations increased the electrode count to 64 and included stimulating circuitry to allow for their use in general neural prosthetic applications, including cortical visual prostheses (Ghovanloo and Najafi, 2004, 2007). Lastly the Huntington Medical Research Institutes also developed their own microelectrode arrays, consisting of between 7 and 16 activated iridium (Brummer et al., 1983) electrodes of 32 to 50-mm diameter and 1–2 mm length, embedded at the base in an epoxy disc (Xindong et al., 1999, 2006). These devices were trialled by a group based at the University of Illinois for developing a visual prosthesis (Troyk et al., 2002). After initial studies on macaques, it became apparent that the bulk of cabling required to tether the arrays to the subcutaneous electronics package would be too great. As a result, the group opted to develop wireless arrays into which the necessary data receiving and transmitting electronics would be integrated (Kim et al., 2006; Troyk et al., 2005).

5.

Wireless neurostimulation

The decision by Troyk and colleagues to abandon a cabled connection between the electrode arrays and stimulating electronics in their visual prosthesis experiments highlights one of the unique hardware challenges faced by visual prosthesis developers; the coordinated stimulation of several hundred or more electrodes (Lewis et al., 2015; Shepherd et al., 2013). In contrast, most other implanted medical devices (IMDs) employing electrical stimulation of human tissue including pacemakers, peripheral nerve stimulators and deep brain stimulators, use far fewer electrodes; in the case of a pacemaker, there may be only a single stimulating electrode. For devices with few electrodes, cabled connections between the electronics and stimulating electrodes represent a viable solution. Indeed, where pacemakers are concerned, this technique has been successfully employed since the 1950s (Greatbatch and Holmes, 1991). Similarly, modern deep brain stimulation systems also employ cabled connections between electrodes and subcutaneously-sited electronics, with the first such devices implanted in the 1970s (Schwalb and Hamani, 2008). As discussed in Section 8, the electrode arrays in Dobelle's visual prostheses were connected via cable to the external electronics (Dobelle, 2000). A significant drawback to such

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directly-cabled connections between implanted electrodes and external electronics in particular (as opposed to those subcutaneously implanted) is the risk of infection, which was a source of ongoing concern for Dobelle's prosthesis recipients (Naumann, 2012). Moreover, the sheer number of electrodes employed meant that the required cabling was bulky; in one patient with bilateral implants, two cables each consisting of 72 individual wires was required to drive the electrodes (Naumann, 2012). As such, the optimal solution remains a wireless connection, and we thus turn our attention briefly to the history of wireless neurostimulation.

5.1.

Early wireless brain stimulation experiments

The first demonstrations of wireless brain stimulation took place in the 1930s, with a number of researchers reporting the successful stimulation of motor cortex and cranial nerves in dogs and monkeys (Fender, 1934; Light and Chaffee, 1934; Loucks, 1933). The technique was based on the same principles of electromagnetic induction exploited by Faraday (1832) to generate electricity, wherein alternating magnetic fields created by a “primary” coil of wire induce current flow and therefore a voltage in a “secondary” coil. In the aforementioned studies, the secondary coil was typically encapsulated in a material such as collodion or rubber, implanted under the skin and connected directly to the stimulating electrodes (Fig. 9). High-current electrical pulses delivered to the primary coil would induce similar, albeit lower-intensity pulses in the secondary coil and subsequently the stimulating electrodes. Interestingly, Loucks demonstrated that it was possible to not only stimulate wirelessly, but he also found that electrical signals from the target tissue could be detected in the primary coil, thus suggesting it was possible to both stimulate and record neural activity over the wireless link (Loucks, 1933). A limitation of the technique employed in these early studies was the very high primary coil currents required to

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induce a sufficiently strong current in the secondary, implanted coil (Newman et al., 1937). Moreover, there was little control over the shape of the resulting stimulus pulse. Improvements on, or variations to this basic method were explored in subsequent years, in an effort to improve the transfer of energy to the secondary coil/s, permit more control over the shape and timing of the stimulus pulse, or to increase the distance between the transmitting and receiving hardware (Gengerelli and Kallejian, 1950; Greig and Ritchie, 1944; Lafferty and Farrell, 1949; Newman et al., 1937). The development of the transistor in 1947 (Riordan et al., 1999) led to further increases in the sophistication of the receiving circuitry, whilst also facilitating significant reductions in its size (Verzeano and French, 1953). These developments ultimately paved the way for the first-in-human implantations of brain stimulation devices that could be operated without requiring a percutaneous wired connection.

5.2.

Wireless brain stimulators implanted into humans

In 1968, two reports were published that described the implantation of wirelessly-operated brain stimulation devices implanted into humans. The first was that of Brindley and Lewin's visual prosthesis (Brindley and Lewin, 1968b), with Delgado's report on human implantations of the “stimoceiver”, combining both wireless brain stimulation and EEG telemetry, published shortly thereafter (Delgado et al., 1968). The stimoceiver was a bidirectional brain–machine interface that utilised a simple FM radio for telemetry. The device was capable of selective stimulation of 3 electrodes over the wireless link, however the implanted electronics were battery powered and both the battery and stimulating electronics were housed within a small external module that was itself connected to the electrodes via a skull-mounted plug. The device was implanted into patients with temporal lobe epilepsy, and was used to correlate EEG signal changes with

Fig. 9 – a: X-ray of a wire coil implanted over the occipital area of a baboon. One end of the coil leads to a silver return electrode plate, with the other end (white arrow) implanted in the motor cortex. b: Experimental animal with implanted wire coil, able to freely move within a cage, itself enclosed within three coils used for activating the implanted coil. The three-coil method was devised to minimise the influence of the relative orientation between the primary and secondary coils on the resulting intensity of stimulus. Image adapted from (Chaffee and Light, 1934) with permission from the Yale Journal of Biology and Medicine.

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the clinical manifestations of seizures, and to identify possible therapeutic surgical targets using stimulation. In 1969 Delgado published a report describing a new device, tested in chimpanzees, that was both powered and controlled wirelessly and was thus fully implanted like Brindley's visual prosthesis (Delgado, 1969). Unlike Brindley's first device, in which a single secondary receiving coil was connected to a single electrode, Delgado's now fully-wireless system facilitated the selective stimulation of up to 3 electrodes, by varying the frequency of the signal in the primary (transmitting) coil. With two implanted receivers, up to 6 electrodes could be selectively stimulated. These new devices constituted an improvement over the simple one-coil to one-electrode method of wireless stimulation, however still did not permit the control or “addressing” of the hundreds of electrodes that it was felt were required for a functional visual prosthesis. Brindley's second visual prosthesis design reduced the number of transmitting and receiving coil pairs to 20 for addressing 75 electrodes (Donaldson, 1973). This system was implanted into a blind human subject in 1972 (Brindley et al., 1972); the results of its testing are discussed in Section 3.4.

5.3. Reducing the number of coils in high-electrode count wireless links Over the same period that Brindley's group designed and implanted their second visual prosthesis, other designs were reported that allowed for the wireless control of large numbers of electrodes using fewer coils. Marg and colleagues (Marg et al., 1970) reported on a system that could address up to 512 electrodes using four transmitter/receiver coil pairs. Similarly, Lin et al. (1972) designed, built and bench-tested a system that could control and power 64 electrodes, again using just four separate coil pairs to deliver power and control signals. To our knowledge, neither system was ever implanted into a human subject. Continued development in wireless links for implantable neurostimulation devices reduced the number of coil pairs required to one, and these were deployed in devices such as the cochlear implant and retinal visual prostheses (Clements et al., 1999; McDermott, 1989). The cortical visual prosthesis proposed by Marg, in a similar fashion to others at the time (Dobelle and Mladejovsky, 1974; Donaldson, 1973; Schimmel and Vaughan, 1971) was designed around an array of surface electrodes embedded in a flexible substrate that could conform to the brain surface. After the work of Schmidt et al. (1996) demonstrated the improved safety and efficacy of intracortical microstimulation for eliciting phosphenes in the blind, the single large-array method of electrode implantation was no longer feasible; the fine penetrating electrodes required for ICMS were typically embedded in a rigid material, which could not conform to the brain surface over a wide area. Thus, the wireless receiving circuitry and stimulating electronics could no longer be combined with the electrode arrays into a single package. Proposed solutions to this problem included separating the wireless receiving and control circuitry from the electrode arrays (Sawan, 2004), or developing small electrode arrays containing complete circuitry for wireless communication

and powering as well as electrode stimulation (Troyk et al., 2005). In the former, a single transmitter/receiver coil pair is used to power and communicate with the implanted electronics. In the latter, a single external transmitting coil communicates with multiple implanted receiving coils, each serving a single electrode array. Both techniques are being exploited in current cortical visual prosthesis designs, which we have reviewed in more detail elsewhere (Lewis et al., 2015).

6.

Closing remarks

The discoveries and developments presented in this manuscript are intended to provide the reader with an appreciation of the long history of scientific achievement underpinning current research efforts in the field of cortical visual prosthetics. Within the scope of a journal manuscript it would be impossible to appraise all the discoveries that underpin such a multidisciplinary pursuit as this, and some topics have necessarily been treated only briefly or left to the reader to pursue further. For example, developments in manufacturing and packaging technologies that permit the construction of water-tight, implantable biomedical devices are also of particular interest and essential to the success of current efforts. The fields of psychophysiology and computer science also form key components of cortical visual prosthesis research, and future developments in these two fields will be critical to ensuring that recipients of these devices enjoy measurable improvements to their quality of life. In the 19 years since the last reported human studies at the NIH, significant progress has been made in understanding the technical, biological and clinical requirements of a cortical visual prosthesis fit for human use. Importantly, it is widely accepted that numerous challenges remain to be solved before such devices will demonstrate unequivocal and long-term clinical benefit, and ultimately obtain widespread regulatory approval. For a detailed treatment of these ongoing (and future) challenges, the reader is referred to a recent review by our group (Lewis et al., 2015) and several others (Cohen, 2007a, 2007b; Fernandez et al., 2014; Schiller and Tehovnik, 2008; Tehovnik and Slocum, 2013). Briefly, significant questions include maintaining the viability of the tissue/electrode interface over the long term, avoiding seizures when concurrently stimulating multiple electrodes, optimising the information content of phosphene-based imagery (including preserving depth information) and efficiently mapping large numbers of phosphenes within the visual field. Critically, it still remains to be seen what a prosthesis recipient will actually perceive during dense, patterned microstimulation of visual cortex.

Acknowledgements The authors would like to express their sincere thanks to Professor Sir Giles Brindley for his review of earlier versions of this manuscript, and for granting permission to use images from his personal archive. We also thank Priv.-Doz. Dr. med. Erhard Lang for his assistance in locating a number of old German manuscripts, and to Professors Arthur Lowery and

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Marcello Rosa of the Monash Vision Group for their comments and advice.

r e f e r e n c e s

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Electrical stimulation of the brain and the development of cortical visual prostheses: An historical perspective.

Rapid advances are occurring in neural engineering, bionics and the brain-computer interface. These milestones have been underpinned by staggering adv...
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