In a typical cochlear implant, flexible lead with stimulating electrodes is inserted in the scala tympani, a fluid-filled cavity in the cochlea. When the electrical stimulation is applied, it propagates through fluid in the scala tympani and across the basilar membrane, separating the scala tympani and the scala media, an adjacent compartment of the cochlea containing the hair cells. Such rather remote operation of existing cochlear implants does not allow fine localized targeting of the hair cells, limiting their pitch resolution. Cochlear implants have not undergone significant changes in their design or function since 1985, when the first multi-channel cochlear implant was developed by Cochlear and approved by FDA. Since then, FDA approved similarly-designed cochlear implants by two other companies, one by Advanced Bionics in 1996 and another by MedEl in 2001. An apparent lack of innovation in cochlear implant is partially due to the fact that, despite their limited pitch resolution, they provide rather faithful reproduction of human speech. The remaining “holly grail” of the cochlear implant industry is a device with sufficient pitch resolution for listening to music. So far, that goal remains outside the reach, at least for the devices based on electrical stimulation of cochlea. As a welcome first step toward an alternative method of cochlear stimulation, a group of engineers at the Fraunhofer Institute for Manufacturing Engineering and Automation in Stuttgart, led by Dr. Kaltenbacher, developed a device that can be placed in the middle-ear to bypass the ossicles (the auditory bones) and provide direct acoustic stimulation of the fluid in the scala tympani. In theory, such a design can: 1) be less invasive, 2) be easily implanted in an outpatient procedure, and 3) potentially provide better sound quality than existing cochlear implants. The implant does require that at least some of the hair cells are still present in the cochlea (unlike the other types of cochlear implants). In order to bypass the bones in the middle ear, the sound is picked up by an externally-mounted microphone, converted to infrared light, passed through the tympanic membrane, picked up by a photo diode, and finally converted back to the sound waves with MEMS-based piezoelectric thin-film cantilevers (see the inset). So far, the engineers are testing individual components of the device, with a finished prototype tests planned for 2014.
Most commonly used neuromodulation strategies, such as the DBS for treatment of Parkinson’s disease or spinal stimulation for chronic pain, use electrical stimulation to mask or override abnormal firing in disease-affected neuronal networks rather than to assist in repairing these networks. In other words, the electrical stimulation is used to treat the symptoms rather than the disease itself. In contrast, two publications (one and two) by Dr. Hentall’s group at The Miami Project to Cure Paralysis describe a novel therapeutic role for electrical stimulation in the brainstem, a region of central nervous system between the brain and spinal cord. Specifically, the electrical pulses were used to stimulate activity of the raphe nuclei, which have an important role in orchestrating anti-inflammatory and neuroprotective effects throughout the central nervous system. The raphe nuclei are composed primarily of serotonergic neurons that have extensive connections throughput the central nervous system, with the raphe magnus projecting to the spinal cord and medial/dorsal raphe nuclei projecting to cerebral cortex and subcortical structures. Due to a high concentration of serotonergic neurons in these nuclei and their common involvement in anti-inflammatory and neuroprotective functions, generalized stimulation of these nuclei results in synergic activation of these neurons and effective induction of biological repair mechanisms. It should be noted that presence of such homogenous neuronal population in the raphe nuclei is rather unique, as most brain regions have heterogenic populations with divergent (sometimes even opposite) functions.
NTZ blog has been paying close attention to neural prosthetic devices aimed at improving cognitive functions. We have presented the beneficial effects of direct current stimulation (tDCS) of the temporal lobe and frontal cortex, DBS of the fornix, and recording in CA3 region coupled with stimulation of CA1 region in the hippocampus. The last-mentioned study was performed using a rat preparation in 2011 by a Prof. Ted Berger at the University of Southern California and Prof. Samuel Deadwyler at Wake Forest University. Merely a year later, the same group of researchers has accomplished a new feat – a closed loop recording and stimulation in the rhesus monkey’s prefrontal cortex, an important location for decision-making and short-term memory processes. The same nonlinear dynamic model (MIMO) was applied for decoding, enhancing, and re-encoding of the firing patterns. To access the prefrontal cortex, the ceramic-substrate multisite electrodes were chronically implanted, targeting the supra-granular layer 2/3 and infra-granular layer 5. Cocaine was used to disrupt cognitive activity, simulating the brain injury. As you can see in the graph above, the memory task performance was fully restored by MIMO-patterned electrical stimulation during the task execution. The far-reaching goal of the project is to replace the memory forming process in the brain area damaged by stroke, dementia or other disorder by using a neuroprosthetic device interfaced to the healthy decision-making area of the brain.
Bionic Vision Australia is a consortium of Australian scientists who are working together on suprachoroidal retinal stimulation device for restoring the lost vision. This effort involves about 150 researchers at the Bionics Institute, Centre for Eye Research Australia, NICTA, University of Melbourne, and University of New South Wales in Sydney. The suprachoroidal approach shares some similarities with the cochlear implants, as in both cases the implants are placed in a fluid-based cavity adjacent to the compartment with sensory neurons. The suprachoroid approach is considered safer and easier than surgically-challenging placements directly above the retina (epiretinal) or below it (subretinal). The analogy with the cochlear implants is not a coincidence, as the Australian researchers have leveraged from their extensive experience in developing the first FDA-approved multi-channel cochlear stimulation device for restoring the hearing more than 30 years ago.
Toward their ultimate aim of implanting the 98-electrode suprachoroidal implant, in May 2012, the Australian researchers reached a significant milestone with an implantation of the early-prototype device in three patients with profound vision loss due to retinitis pigmentosa, an inherited condition. While the functionality of the prototype is rather limited (24-electrodes and a lack of wireless interface to the camera), it will enable psychophysics studies to carefully examine the visual percepts and allow researchers to develop appropriate visual processing strategies in preparation to implantation of the fully-functional device in 2013 or 2014. The R&D effort is being supported by a $42 million grant from the Australian government and technology-sharing agreements from Cochlear Ltd.
One and a half years ago, NeuroTechZone reported on initial success of subretinal implants from the Retina Implant AG in three retinitis pigmentosa (RP) patients from Germany. The international multi-center phase of the clinical trial with the wireless implant Alpha-IMS was initiated in late 2011, involving two additional sites in Germany, two sites in London, UK and one site in Hong Kong, China. Altogether, 26 patients have received subretinal implants in the trial. The first two UK patients with RP were implanted in April 2011 and the UK doctors are recruiting additional 10 patients. The first Chinese patient was implanted on February 2012, with two more to follow. Additional sites in Hungary, Italy and the United States will soon join the trial. The data from recently implanted patients indicate a restoration of useful vision in daily life. Many of them experience visual perception in both dim and bright environments. Some patients have reported the ability to see objects 30 feet away and to read numbers on a pair of dice. Unexpectedly, one of the British patients reported having dreams in color for the first time in 25 years since becoming blind.
Combining several therapies to build a rehabilitation treatment plan for neurological conditions is nothing new. However, combining a variety of technologies into a treatment plan to produce functional outcomes is an emerging theme among innovative rehabilitation professionals. The roots of combining the rehabilitation with electrical stimulation to improve motor re-learning come from the pioneering work by Dr. Randolph Nudo and Dr. Alvaro Pascual-Leone in 1990es.
Recently, this approach was applied by combining the robotic therapy with electrical or magnetic stimulation by a team of researchers lead by Dr. Lumy Sawaki at the University of Kentucky in Lexington. This new neural rehabilitation technique capitalizes on “neuroplasticity,” which refers to the brain’s ability to reorganize itself by forming new neural connections to compensate for injury and disease. Dr. Lumy Sawaki, MD, PhD, an Associate Professor in the Department of Physical Medicine and Rehabilitation at the University of Kentucky, has been exploring how combining technologies in the rehabilitation setting may help her patients regain functional movements. This new therapy is based on previous work she had done involving CIMT, constraint-induced movement therapy. Dr. Sawaki was the lead author on a CIMT study published in the journal Neurorehabilitation and Neural Repair. In this study, each of the 30 participants was evaluated using transcranial magnetic stimulation (TMS), a non-invasive method to excite neurons in the primary motor cortex. In the CIMT therapy study, Dr. Sawaki and collaborators used TMS to map the area of the brain that controls a particular muscle and compared this map to previous patterns of activity. As the patient’s ability to perform a certain movement improves, these brain maps confirm the reorganization of the associated area of the brain. Focusing on hand motor function of sub-acute stroke survivors, they observed changes within the functional activity of the brain for those who used CIMT.
Building on this previous work, Dr. Sawaki and her research team are evaluating the combined approach to stimulate the brain with two painless and non-invasive methods: the magnetic stimulation with TMS and the electrical stimulation with transcranial direct current stimulation (tDCS), to develop a new neural rehabilitation therapy for chronic survivors of neurological trauma from stroke, brain and spinal cord injuries. In this new therapy, the TMS and tDCS is applied along with robotic movement therapy, such as body weight supported treadmill training. Dr. Sawaki is using TMS and tDCS to stimulate the area inside the motor cortex that controls movement of a targeted muscle. By applying multiple stimuli and monitoring the muscle response combined with robotic therapy, the investigators are attempting to determine if this combination will result in higher functional benefit.
Conclusive evidence is still lacking but it brings the promise of combined neural rehabilitation therapies paving a new path for how we approach complex neurological conditions in the rehabilitation setting. Click here to read more about Dr. Lumy Sawaki’s research and new neurorehabilitation therapy.
Central-nervous-system based neuromotor prosthesis (NMP) holds a great deal of promise for complete spinal cord injury (SCI) yet is still far from the clinical use. Cortical-level NMP uses direct cortical recording and requires craniotomy for implanting a microelectrode array in the motor cortical area of an injured person. First successful human trial of the cortical NMP in a quadriplegic person, the BrainGate, was done by Dr. Donoghue and colleagues back in 2006. Last year, Dr. Edgerton and colleagues have applied a spinal NMP to train a paraplegic person to stand and walk on a treadmill. As these cortical and spinal NMPs are reaching maturity, the question emerges, whether all people with SCI can benefit from this technology. In this post, I will try provide my perspective about the potential technology users.
SCI has different severity, motor complete or incomplete, and occurs at different spinal levels, from cervical to thoracic and lumbosacral, resulting in quadriplegia or paraplegia. NMP is potentially most viable for motor-complete SCI since people with incomplete SCI can benefit from extensive rehabilitation training. Quadriplegics with motor-complete SCI would likely benefit the most from this technology. One of major challenges for implementation of cortical NMP for quadriplegics is the availability of real-time adaptive decoding algorithms for controlling the body balance, needed to enable standing and locomotion. As a quadriplegic person completely loses his/her posture control, it is unlikely that they could use existing decoding algorithms for cortical NMP for standing and stepping. Still, such a person can use the cortical NMP for controlling an external device or an upper limb (through stimulation of peripheral nerves or muscles). Volitional control of an individual hand muscle by this kind of cortical CNMP has already been demonstrated in non-human primates by Dr. Fetz and colleagues.
It is not clear whether paraplegics can benefit from the NMP technology to the same degree as quadriplegics. As paraplegics have useful hand and arm functions, cortical NMP might be too risky and invasive of a procedure to justify the potential benefits. Perhaps, a spinal NMP controlled by a hand or a processor that interprets the person’s movement intent can be more beneficial for standing and walking. In a spinally-intact person, the leg movements and locomotion require no visual feedback and are adjusted in time and space through a local feedback circuitry in lumbo-sacral region of spinal cord. Provided that this feedback loop is intact in the paraplegic person, would be extremely beneficial to use this loop along with the spinal Central Pattern Generator (CPG) for enabling the locomotion. Recent human studies by Edgerton and others indicate simply turning these spinal neural circuits ON and OFF might not be enough for standing and/or stepping. Hopefully, with more robust decoding and encoding algorithms, the spinal NMP might become a viable clinical solution for paraplegics.
Considering these arguments, I would like to suggest that an ideal candidate for cortical NMP would be a quadriplegic, while an ideal candidate for spinal NMP would be a paraplegic.
Upper (e.g. bronchial) airways become constricted in people with asthma or chronic obstructive pulmonary disease. The bronchial smooth muscle contraction is mediated by the parasympathetic nervous system, while the relaxation is mediated by the sympathetic nervous system. The periaqueductal gray matter of the midbrain (PAG) and subthalamic nucleus (STN) are involved in maintaining the bronchial relaxation. The electrical stimulation of the PAG is approved for chronic pain and electrical stimulation of the STN – for movement disorders (Parkinson disease and dystonia). A new study by a group of neurosurgeons from Oxford, United Kingdom evaluated the effects of the PAG and STN stimulation with DBS electrodes on the bronchial airway function. They found that activation of both brain structures in awake human subjects produced similar increases in the airway flow of 10-12%, with some patients exhibiting even larger increases (up to 30%). While similar effects were seen in both PAG and STN, the used stimulation frequencies were quite different: 7-40 Hz in PAG and 130-180 Hz in STN. It is important to mention that PAG is considered to be a major integration center for multiple autonomic functions, such as cardiovascular responses, thermoregulation, respiration, bladder and bowel voiding, arousal, and rapid-eye-movement (REM) sleep. This study raises an important question whether asthma is a neurological disorder that can be treated by neuromodulation?
The neuroscientists at UC Berkeley conducted the study in 15 patients with epilepsy or brain tumor, in which the subdural electrocorticographic (ECoG) recordings were used for deciphering the speech processing in the cortex. Brain activity was induced in the superior and middle temporal gyri, the cortical regions involved in speech comprehension, by listening to words. Each word was played to a patient for 5-10 minutes to collect enough data for analysis. The spectral features of the sounds were used for linear and non-linear regression algorithms in order to reconstruct the words from the pattern of brain activity. The reconstructed words were intelligible enough to recognize them, although they sounded as if spoken under water. The proposed technology is still rather immature but one day it hopefully would be able to convert the ECoG activity in the auditory cortex into spoken language for patients with a stroke, locked-in syndrome, and other disorders resulting in a paralysis of their vocal cord and arms (think of Stephen Hawking).
During stimulation, the applied electrical charge induces similar flows of multiple extracellular cations (K+,Na+ and Ca2+) in the electrode vicinity. This is rather counter-productive as these cations play varying roles in the initiation and propagation of action potentials. As a result, a significant percentage of applied electric charge is being wasted. Now, scientists at MIT and Harvard Medical School have reported a way to alter the cation concentrations using commercially available cation-selective resin solutions deposited on planar electrodes. In one experiment, they applied small positive DC current (≤1µA, 10 to 100 times below the nerve activation threshold) to a centrally-located calcium-selective electrode for 1 min to deplete Ca2+ concentration from the fluid surrounding the nerve. Immediately thereafter, they applied the supra-threshold electrical pulses between two lateral uncoated electrodes, while the central electrode was off. The researchers achieved a 70% decrease in the amount of current required for reaching the nerve activation threshold. In another experiment, the K+– and Na+-selective electrodes were used to deplete the concentrations of these ions at some distance from the stimulating electrode. Such cation depletion caused a complete conduction block for 10 min after applying a cation-depleting DC current of 1µA for 5 min. Both K+– and Na+-selective electrodes were equally effective in blocking the action potential propagation. This finding could have important applications in shutting off the nociceptive neural activity in relieving chronic pain. Finally, the developed cation-selective electrodes have two important features making them attractive for neuroprosthetic applications: 1) they can be microfabricated and 2) they do not require a chemical reservoir for their operation.
About 3 -4% of the general population has or will develop a cerebral aneurysm, with most are without any symptoms. Aneurysm is an enlarged area of a blood vessel that usually develops at a branching point of artery and is caused by constant pressure from blood flow. It often grows gradually and becomes weaker as it stretches. Rupture of a cerebral aneurysm causes bleeding into the brain, often leading to a stroke. Endovascular embolization using micro-coils has emerged as a successful preventive treatment for aneurysms. The micro-coils are made from platinum wire (thickness 20–120 μm) wound at diameters of 200–500 μm for length up to 50 cm. Once the coil is inserted through the artery into the aneurysm, it forms a randomly tangled globe that promotes clotting of blood, thus preventing further inflow of blood and pressure rise. In about half of implanted patients,
the embolization process fails within 18 months, requiring frequent checks for the blood entry into the aneurysm using expensive, invasive, and potentially toxic methods, such as X-ray angiography and computer tomography. The group of Dr. Takahata at the University of British Columbia has reported a new method for monitoring blood entry into aneurysms, which is simple and inexpensive enough for frequent monitoring at home. In their method, the RF resonance of the micro-coils is used as a moisture sensor. The RF resonant circuit is formed by self-inductance combined with parasitic capacitance, which is affected by tissue permittivity around the coil. At 100 MHz, for example, the dielectric constant of blood is 25 times higher than that of fibrous tissue. The RF coupling of the micro-coils would be done with an external antenna attached to the head of a patient. The present study was conducted using animal muscle tissues, with a clinical device
anticipated in 2-3 years.
As the number of people with Alzheimer’s disease (AD) is rising with aging population, there is an increasing urgency in developing an effective approach to slow its progression. Despite the efforts by pharmaceutical companies, currently approved drugs provide only modest effects and are often difficult to target to the brain without avoiding the systemic side effects. A possibility of using electrical stimulation for combating the disease has not been considered until a serendipitous discovery reported in 2008 by Dr. Andres Lozano, a neurosurgeon at the University of Toronto. He applied the DBS stimulation at the satiety-controlling region of the brain, the fornix, in a patient with morbid obesity with a hope of reducing the sensation of hunger. Surprisingly, the psychological tests have shown a significant improvement in patient’s memory. The follow-up study in AD patients, published in 2010, showed that the fornix stimulation can slow the memory decay. The authors of the study speculate that possible mechanism of action involves plasticity in the limbic circuitry counteracting the AD-related neurodegeneration. As a result of these findings, a startup company called Functional Neuromodulation Inc. was formed in 2010 to commercialize the DBS use in the fornix for AD patients. It recently obtained funding from Genesys Capital and Medtronic to conduct the second clinical trial in the AD patients. It is worth mentioning that other companies, such as Medtronic and St. Jude Medical, have considerable intellectual property on electrical stimulation of other limbic areas, such as the anterior thalamic nucleus, internal capsule, and subgenual cingulate cortex, which may also play an important role the memory formation process. We will anxiously await further developments in the use of DBS to counteract the progression of AD.
The quest for highly functional neuroprosthetics in activities of daily living has implicitly assumed that the neural interface would include both motor and sensory (i.e. tactile and proprioceptive) functionalities. It is likely that for reaching and grasping tasks, the dynamic sensorimotor programs will need to be developed to enable dexterous control. Interestingly, the neural decoding, stimulation, and hardware principles for sensorimotor interfaces are often developed in isolation in motor-only or sensory-only studies. In this week’s issue of the journal Nature, a new study was published by Prof. Nicolelis group from Duke University attempting to create a bi-directional sensorimotor neural interface for reaching tasks. Primates used both direct brain motor control and artificial tactile sensory feedback delivered back to the brain to complete the task. Both the motor and sensory channels bypassed the subject’s body, effectively liberating a brain from the physical constraints of slow nerve implse propagation through the nervous system. Potential use of such bidirectional control is not limited to artificial limbs and can include fast communication with a variety of external sensors and actuators.
Migraine is a highly prevalent neurological disorder, affecting more than 10% of people (6% of men and 18% of women) worldwide. It is not surprising, therefore, that all three of the major neurotech device manufacturers, Medtronic, St. Jude Medical, and Boston Scientific, have evaluated their implantable stimulators for treatment of his chronic condition. Multiple areas have been targeted for treating migraine; with most common ones being the occipital nerves and the cerebral cortex. The latter approach is usually accomplished non-invasively with the transcranial magnetic stimulation and is most helpful for patients whose migraines begin with an aura, a condition characterized by flashing lights or other visual (or sometimes sensory, motor or verbal) disturbance. The occipital nerve stimulation is more generally applicable to migraine sufferers, and involves a chronic implantation of the stimulating device. The clinical trials have been performed to see whether any of the devices could clear at least one of two FDA-mandated thresholds: a 50% reduction in migraine severity or a 50% reduction in migraine frequency. Boston Scientific’s pivotal trial PRISM was completed in 2009, showing no significant improvements. Medronic’s pivotal trial ONSTIM was completed in 2010, indicating that 39% of patients achieved 50% reduction in migraine frequency. St. Jude Medical’s pivotal trial ended in June 2011 and was, perhaps, the most successful of the three: they reported an overall 28% reduction in migraine frequency and 42% reduction in migraine severity. Although these results are insufficient for the FDA clearance, the St. Jude Medical’s Genesis device was able to receive the European CE mark approval in September 2011. This gives the first-mover advantage to St. Jude Medical in Europe, but the battle for the lucrative US migraine market is still waging on.
The 2011 meeting of the International Neuromodulation Society, which took place in London, England in May 2011, featured a large number of oral and poster presentations offering updated technical and clinical information on neuromodulation topics. There was also a full day of sessions devoted to commercialization, investment, and industry issues affecting neuromodulation startup firms.
But as is the case with many meetings that draw attendance from different fields of endeavor, there was as much to learn from the informal scuttlebutt going on between sessions as there was from the posters and oral presentations themselves. We offer here some of our observations based on random comments from attendees.
After the Sunday session on future innovations in neuromodulation, some attendees were perplexed by Greatbatch Inc.’s efforts to launch a new spinal cord stimulation device company, called Algostim LLC. Given that Greatbatch supplies components such as batteries and leads to many manufacturers of implanted neurostimulation systems, it raised the question as to why Greatbatch would want to compete with its customers. Greatbatch CEO Tom Hook made the case that by incubating new device startups that will eventually be spun off, Greatbatch will cultivate a greater customer base in the future. It will be interesting to see how that situation plays out.
That controversy might have presented an opportunity for component supplier Cirtec Medical to drum up business, had they have more of a presence at the event. But that company has been hit by the departure of some key staff members, including its former president Barry Smith.
There was also some discussion on the competitive positioning of new entrants in the spinal cord stimulation business such as Nevro, Spinal Modulation, and Neuros Medical. Several attendees thought that Neuros has a sound technology base, though probably the smallest market opportunity of the three. There was speculation that Nevro and Spinal Modulation might be ripe targets for acquisition by existing players in the SCS market. It will be interesting to see if either firm makes it to the market approval stage, let alone profitability, before being snapped up by one of the big three.
Speaking of spinal cord stimulation, perhaps the most profound observation we heard at the conference was by Robert Levy of Northwestern University, who noted that the SCS systems that existed five to 10 years ago, which serve as the basis for many long-term pain studies, represent the worst case scenario. Today’s SCS systems, with their greater specificity, targeting capabilities, and control over stimulation parameters, offer a far better outcome for patients and vendors alike.
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