In the DARPA-led project REMIND, Prof. Ted Berger from the University of Southern California and Prof. Samuel Deadwyler from Wake Forest University have been developing an innovative type of neural prosthetic device for restoring and enhancing the formation of long-term memories. Their strategy is to build a computational model of the information processing in the hippocampus and use it as a substitute for normal memory encoding in people with brain trauma, dementia, stroke, and other disorders affecting learning. In their new work, the scientists have described achieving an important milestone – improving the memory formation in laboratory rats. In the performed behavioral tests, the rats were trained to remember the lever location and, after being distracted, had to recollect which lever to push. Two 16-electrode devices were implanted bilaterally for recording communication between the CA3 and CA1 sub-regions of the hippocampus. After the CA3 neuronal activity was recorded during successful recollection of the lever location, it was played back during the next recollection trial by stimulating the neurons at the CA1. And the rats displayed an amazing 20% improvement in their memory recollection (see the figure). Then, the scientists did something even more remarkable. They temporarily blocked the intrinsic CA1 activity (using a glutamate receptor antagonist), fully substituting it by the electrical stimulation. And the animals were able to remember the lever location equally well or even better than with their natural CA1 processing! These findings generate a lot of excitement, but the scientists are still facing a long road ahead to develop a fully functional replacement for hippocampus. One major challenge would be to build a scaled-up device for recording the activity of thousands of neurons in the hippocampus. Another hurdle, perhaps even more significant, would be to create a memory encoder that can go beyond replaying the previously-remembered tasks and to create brand new memories. After all, learning something new is a lot more exciting than, say, reciting the Pythagorean theorem for the N-th time.
About one third of epilepsy sufferers are refractory to drug treatment. When drugs are ineffective, these people find their hope in brain-applied electrical stimulation. Several commercial neuroprosthetic devices have been successful in providing at least partial relief. They include a vagal nerve stimulator (VNS) from Cyberonics Inc., and a deep brain stimulator from Medtronic Inc., and cortical stimulation device from NeuroPace Inc. These devices are surgically implanted and cut the number of seizures in half or more in about 40% of drug-resistant patients. Currently, there is no neurological test to predict who will benefit from electrical stimulation. To solve this problem, Dr. Christopher DeGiorgio, a neurologist at UCLA, decided to use an external stimulator to estimate whether the epilepsy sufferers would benefit stimulation therapy before an invasive surgery is performed to implant a permanent device. His stimulator activates a superficially-located trigeminal nerve, a large cranial nerve that projects to key parts of the brain that modulate seizure and mood. The stimulation is applied at the forehead, while the electrode leads are connected to a small wearable pulse generator. According to the initial clinical test, the stimulator has similar efficacy to the implantable VNS. A positive side-effect of trigeminal nerve stimulation is an improvement in mood, which is important as many epilepsy patients suffer from depression. A startup company NeuroSigma Inc. has licensed the approach to stimulate the trigeminal nerve for epilepsy, depression, and PTSD, and is developing an implantable version for those who find relief with the externally-applied device.
Stroke is the third-leading cause of death in the U.S. and the leading cause of disability. While some 1.5 million people in the US report stroke-like symptoms annually, half of them have actually not suffered a stroke. Making a reliable assessment of stroke in just minutes would provide timely information for treating the victims faster, at lower cost, and with less risk. Jan Medical developed the first and so far the only portable brain sensing device for rapid detection of ischemic stroke. The device is aimed to be used in the ER or ambulance, before a thorough evaluation can be made in a hospital setting with a CT or MRI. The device operation is based on an interesting principle of detecting the ultrasonic waves emitted by the skull. The device does not measure back-reflection of the emitted ultrasound from the brain; instead, it measures natural mechanical vibrations of the skull. These vibrations are generated by a pressure wave of blood rushing from the heart toward the skull during each pulse. In 5 minutes, the device collects enough information to detect a variety of cerebrovascular anomalies: an intracerebral or subarachnoid hemorrhage, epidural or subdural hematoma, intracranial aneurysm, arteriovenous malformations, ischemic stroke, or transient ischemic attack. The device consists of two primary components: a headset with sensors and a controller for decoding the collected ultrasonic information connected to a computer. Jan Medical markets its device primarily for early detection of stroke as well as the traumatic brain injury, such as sports-related concussion that is often not detected on the field leaving it to a discretion of a team physician to clear the player for return to the game. The device can also be used for rapid military diagnostics of traumatic brain injury at the battlefield.
Earlier this month, DARPA released a call for proposals addressing a key challenge in the brain-machine interfaces (BMI) – the reliability of cortical electrode-tissue interface. As seen in the chart above (taken from this DARPA presentation by Prof. Jack Judy), existing intracortical electrode arrays (such as BrainGate) can extract a lot of information from the cortex (1500 events/s and more) but their performance drops off by 50% in about one year after their implantation. By 3-5 years after implantation, performance further deteriorates to a point where their informational flow is no longer above that of peripheral nerve electrodes. The DARPA initiative aims to explore novel revolutionary approaches to improve the long-term reliability of neural recordings to sustain high information flow needed for controlling an artificial hand or arm. The ultimate goal of the initiative is to develop the intracortical array that can provide the life-long information flow of 2000+ events/s to control the 22-degrees-of-freedom artificial arm recently developed by DARPA. Achieving this very ambitious goal will likely require a concerted effort of multiple research groups working together on different aspects of the problem, ranging from the design of novel biocompatible and neurotropic/ immuno-suppressive electrode materials to development of robust non-linear state-dependent decoding algorithms and advanced techniques for device packaging and wireless telemetry.
According to a recent MedGadget post, a Colorado-based company Clarimedix has developed a BandAid-looking device that can be attached on the neck’s skin and emits infrared light onto the carotid artery. The device is being evaluated for treatment of Alzheimer’s disease. The company’s website provides scant scientific explanation for its therapeutic action indicating just that light modulates the production of nitric oxide (NO) in the brain . To expand on their rationale, I examined recent literature on this subject and sketched the diagram (see the image) illustrating the hypothetical mechanism of device’s action. According to one recent review, NO has two opposing effects on neurons. On one hand, NO is involved in neuroprotection by activating the Akt, Bcl-2, and MAP kinase survival pathways. On the other hand, NO inhibits mitochondrial respiration (by blocking the activity of cytochrome c oxidase), therefore depleting neurons of energy and ultimately leading to their inflammation and death. The harmful effect of NO on mitochondrial respiration can be reversed by light, at least in vitro. So, by illuminating the carotid artery, the Clarimedix device modulates the NO release and possibly helps to suppress the progression of neuroinflammatory diseases, such as multiple sclerosis, Alzheimer’s and Parkinson’s diseases. The evidence for its therapeutic action is very weak at the moment but non-invasive nature of the therapy will hopefully allow for a quick and inexpensive clinical trial.
Glioblastoma is the most common type of brain tumor affecting 0.002-0.003% of general population. In glioblastoma, the astrocytes (neuron-supporting glial cells) turn into cancerous cells, start to divide frequently and gradually form a large mass pressing against the brain. Glioblastoma is a challenging disease to treat as dosages of radiotherapy and chemotherapy are limited by their toxicity to the brain tissue. The use of alternating electrical fields is a novel approach that aims to suppress the division (mitosis) of malignant cells while sparing non-dividing neuronal cells in their vicinity. An Israeli-based company NovoCure Ltd. developed a stimulation device, Novo-TTF, which delivers alternating electric fields through insulated electrodes attached on the scalp surface. The scientific foundation of this approach comes from the study by the Technion scientists showing that alternating electrical fields can stop the cells from dividing and can even destroy them, if the cells are oriented roughly along the field direction. Importantly, the dividing cells inside the blood vessels appear to be unaffected. The key concern for the therapeutic use of alternating electric fields relates to their effects on neurons. At low frequencies, under 1 kHz, alternating electric fields stimulate neurons. As the frequency of the electric field increases above 1 kHz, the field can better penetrate through the cellular membrane, and its effect on neuronal excitability is diminished. At even higher frequencies, above 100 MHz, the brain exposure becomes localized and significant local heating can occur. Faced with these possible side-effects of low and high frequencies, the scientists decided to stick with intermediate frequencies of 100–200 kHz. The electric fields at these frequencies might be relatively safe as long as their intensity is kept below the threshold for inducing the pore formation in the cellular membrane, through a phenomenon called electroporation. A recently completed phase III trial of the Novo-TTF device alleviates some of these concerns by showing no change in incidences of headaches or seizures in patients. The device is likely to be approved for use in the US within the next three months.
Since 2005, DARPA (the Defense Advanced Research Projects Agency) has invested more than $100M into development of the brain-machine interfaces (BMIs) by sponsoring two programs, Revolutionizing Prosthetics and Human-Assisted Neural Devices. Most of that funding went into creation of two BMI-controlled artificial arms – the 10-degrees-of-freedom (DoF) DEKA “Luke” Arm by DEKA R&D Corp. and the 22-DoF Modular Prosthetic Limb (MPL) by Johns Hopkins University together with University of Pittsburgh and California Institute of Technology. A smaller effort to develop the 3-DoF BMI-controlled artificial arm is also underway in Germany by the company Otto Bock HealthCare GmbH. It now appears that DARPA’s investment into neuroprosthetic control of the arm may begin to materialize as early as this summer. The BMI control of the MPL arm will be made possible by the array of penetrating electrodes implanted into the motor cortex of five quadriplegic patients. The silicon-based array will record the multi-unit activity in the cortical area that controls the arm movement and the recorded information will be used to predict the intended direction and force of movement. Penetrating silicon-based arrays have been already successfully tested in monkeys, demonstrating the feasibility of decoding the intent of different movements from cortical signals. The biggest remaining problem is a rapid deterioration in the quality of neural recordings from cortical arrays, ranging from several months to a year. A range of strategies can potentially overcome this problem: 1) by making the electrodes less stiff, 2) by removing the wires tethering the array to the skull, and 3) by using a biomimetic array coating to improve its biocompatibility and reduce the immune response. It is unlikely that any of these novel strategies will actually be used in the first generation of cortical arrays for the MPL control. Nevertheless, the upcoming clinical trial will be a positive event for the BMI R&D community after suffering a setback from the failed BrainGate trial three years ago. Progression of the BMI-MPL clinical trial will be closely monitored and guided by the FDA, which, after extensive talks with DARPA, recently created the Innovation Pathway specifically for such pioneering and transformative medical technologies. By utilizing this Pathway, the FDA aims to cut the premarket approval process time in half (to 150 days or less), suggesting a smooth commercialization path for the BMI-MPL after conclusion of its clinical trials.
On the heеls of the previous post, here is another news bit on the topic of retinal implants. Over the years, we have witnessed a variety of approaches being applied for retinal stimulation, including the epiretinal, subretinal, and suprachoroidal. One feature, however, remained unchanged in those varied types of implants – a planar geometry of the stimulation array. At least until now. As the competition in the retinal implant sector is heating up, the issues of low-power operation and improved electrode contact with retinal neurons is fueling the development of stimulation arrays featuring the 3D geometries. Improved charge delivery to retinal neurons has been achieved a few years ago by fabricating the protruding 3D nanoelectrodes in Daniel Palanker’s lab at Stanford University and at Dong-Il Dan Cho’s and Sung June Kim’s labs at Seoul National University. Now, preparing to reach even deeper into the retina, the Israeli company Nano-Retina Inc., co-founded by Rainbow Medical Ltd. and Zyvex Labs. , is developing the Bio-Retina implant featuring the array of 100-µm-sized penetrating electrodes. Their length should allow the electrodes to reach the layer of bipolar cells that are spared in AMD and other degenerating retinal disorders. The first-generation array will have 24×24 electrodes and the second – 72×72. Power to the device will be delivered wirelessly using the infrared light beamed from the glasses. To expedite their efforts in developing the low-power IC chip with the built-in photodetector array and power telemetry, Nano-Retina has teamed up with CMES (Centre Suisse d’Electronique et de Microtechnique), a non-profit R&D center in Switzerland. According to their (perhaps too optimistic) estimates they plan to have the functional device ready for clinical trials by 2013 and even have estimated the target price of $60K for the Bio-Retina implant. We wish the best of luck to this young ambitious company, hoping it has what it takes to develop a device from scratch in such a short period of time.
The BCI encompasses multiple types of neural technology united by a common purpose of assisting, augmenting, or repairing human cognitive or sensory-motor functions at the cortical level. Taking its roots from the EEG interfaces in early 1970s, the BCI field has gradually grown to include other non-invasive techniques, such as the NIRS (near infrared-spectroscopy), fMRI (functional magnetic resonance imaging), and MEG (magnetoencephalogram). It has also evolved to include the invasive technologies, such as the electrocorticogram (ECoG) and penetrating cortical electrodes. In 2010, an international committee, headed by Dr. Gerwin Schalk of the Wadsworth Center (Albany, NY), critically evaluated the trends and developments in the BCIs by focusing on its novel applications and technological improvements. The committee examined 57 submissions and selected the winner of 2010 BCI Research Award – a team led by Dr. Guan Cuntai from A*STAR, Singapore – for his work on motor-imagery based BCI coupled to a robotic arm and used for rehabilitation after stroke. The 2011 BCI Research Award will be awarded during the 5th International BCI Workshop on Sept. 22-24, 2011 in Graz, Austria. In the analysis of nominations for the 2010 award, the EEG is clearly the predominant technology accounting for 75% of nominations, while the fMRI and ECoG accounting for 3.5% each, NIRS accounting for 1.8%, and penetrating electrodes accounting for 0.9%. Current philosophy in the BCI development is dominated by four assumptions, stated in a recent article by Prof. Jon Wolpaw of the Wadsworth Center: (1) intended actions are fully represented in the cerebral cortex; (2) neuronal action potentials can provide the best picture of an intended action; (3) the best BCI is one that records action potentials and decodes them; and (4) ongoing mutual adaptation by the BCI user and the BCI system is not very important. According to Prof. Wolpaw, these assumptions are flawed. Indeed, much of the motor control occurs at the spinal cord, brainstem, and deep brain levels. Further complication for BCI is that the cortical involvement in the motor control is state-dependent and continually adapts to optimize the performance in different tasks. Present generation of BCI algorithms do not account for such state-dependent and performance-driven adaptations therefore their effectiveness quickly degrades over a period of several days. Yet another level of complexity for decoding of cortical signals stems from the profound slowly-developing plasticity in the motor cortex after the stroke or spinal cord injury. Fortunately, novel adaptive learning algorithms, like those in the IBM’s Jeopardy-winning computer Watson, continue to grow in sophistication and eventually should attain the adaptability needed for handling the challenges of BCI.
The fear is one of the strongest emotions that drive our behavior. And the amygdala is the central hub for processing the fear responses. How would our life be changed if we were to lose both of the amygdalae? While the animals can be deprived of fear by knocking out Stathmin, a cytoskeleton regulatory protein concentrated in the amygdala and other parts of the fear circuit, these animals cannot report on their internal subjective experience. Unfortunately, no drug is presently safe enough for a temporary amygdala inactivation in humans. Our understanding of a human condition without the amygdalae has been, therefore, rather limited, relying on a handful of patients with a rare genetic disorder, the Urbach-Wiethe disease, which produces bilateral calcifications on the medial temporal lobes, ultimately leading to a destruction of the amygdalae. One of these patients, a woman called S.M., has been studied extensively since 1994 and provided the wealth of psychological and neurological information about her condition. During the course of an extensive psychological evaluation, she reported feeling upset, angry, and irritable, but on no occasion did S.M. experience any fear, guilt, or shame, induced either by real-life experiences (being held up at knife point and at gun point) or by unpleasant thoughts (e.g. about dying). These findings suggest that because of her amygdala damage, S.M. became immune to the devastating effects of posttraumatic stress disorder (PTSD). Similarly to S.M., the Vietnam War veterans with considerable damage to the amygdala have a lower occurrence of PTSD, as described in this Nature Neuroscience 2007 paper. Moreover, when PTSD patients are provoked to recall their traumatic memories, they exhibit an increased activity in the amygdala and the head of the caudate nucleus, as reported in this recent fMRI study. Overall, there is a considerable body of knowledge suggesting that the amygdala inactivation, perhaps through chronic neuromodulation, could be an effective method for PTSD treatment.
The present-day neuromodulation technology has been around for 25 years despite the advances in microfabricaion methods and electronics. In part that is due to a lack of novel scalable platform technologies with proven reliability of electrode-tissue interface, interconnects, and packaging. One of such platform technologies is now being developed by Dr. John Parker at the Sydney-based Implant Systems Group of the Australian research center NICTA. Leveraging from the cochlear implant technology, developed by the Cochlear Corp., Parker and his coworkers are developing a modular platform consisting of the multi-channel electrodes, sensors, actuators, processing elements, and packaging. Among the novel features of this platform are: a novel method for microfabrication of the electrode arrays involving the wire electrodes sawn into polymer yarn, novel biocompatible chip-scale hermetic packaging, and novel ASIC architecture for highly distributed neurostimulation systems employing optical data transmission. Targeted neuromodulation applications for this platform technology range from movement disorders (Parkinson’s disease and essential tremor) to obesity and depression. Perhaps because of a relative simplicity of epidural spinal implantation and a limited number of required stimulation channels, the chronic intractable pain was chosen as the first target application of the technology. The INS2 device will include all key components of the platform including the yarn-woven electrodes with recording and stimulation capability, the ASIC chip, and a rechargeable battery with power telemetry. The human trials will begin sometime in 2011. If successful, the technology will be commercialized by a new spin-out company Saluda Medical.
Obstructive sleep apnea (OSA) is a condition in which breathing is periodically obstructed during sleep, often due to a prolapsed tongue or swollen throat. OSA affects 3-5% of people (18 millions in the US alone) and is often associated with obesity and old age. The hypoglossal nerve (HGN) controls the tongue and soft palate muscles. The closed-loop HGN stimulation, synchronized with the inspiratory phase of respiration, was shown (by Johns Hopkins U. researchers in mid-90es) to reduce the severity of OSA. In 1996-1997, Medtronic Inc. tested the first implantable HGN stimulator, Inspire I, in humans but soon abandoned the device due to concerns about its safety. Fast-forward to 2010: we have an expired patent on the HGN stimulation and several companies vying for dominance in this lucrative market. Charging ahead of the competition is a Medtronic’s spinout Inspire Medical Systems, with its device, Inspire II, that just received the CE Mark for clinical use in Europe. Not far behind are the Apnex Medical and ImThera Medical, who are undergoing clinical trials for their versions of the HGN stimulation devices. It is worth mentioning that other neurostimulation technologies are being applied for sleep apnea. Cardiac Concepts Inc. is developing a device for the phrenic nerve stimulation to restore a more natural breathing pattern in patients with the central sleep apnea, a related medical condition. Inspiration Medical Inc. holds several patents for the diaphragm pacing as yet another method for OSA treatment. Finally, there are some less-invasive approaches including tongue stimulation with sublingual electrodes and the repelling magnetic implants in the tongue base and posterolateral pharynx. Perhaps, it is too early to predict which of the technologies will ultimately prevail, so let’s not lose our sleep over this for now.
the Active Book implant uses novel shape for implantation into spinal column to record from and stimulate the spinal roots.
A device prototype has been fabricated for implantation into human spinal column. It rests over the posterior and anterior (sensory and motor) spinal roots and allows recording from as well as selective stimulation of multiple spinal roots. The work is spearheaded by Prof. Nick Donaldson and Prof. Andreas Demosthenous at the University College London, UK. In collaboration with engineers from Freiburg University and the Tyndall Institute in Cork, they developed a device that includes a VLSI chip for processing the neural recordings and generating the electrical stimulation pulses. The VLSI chip is hermetically sealed into a can enclosure. Hermeticity of the enclosure is monitored using a humidity sensor. The chip feedthroughs are interconnected with the electrodes using wire bonds. The chip, wires, and electrodes are encapsulated into a soft shell, made presumably from silicone or epoxy. The electrodes are fabricated from platinum foil using laser etching and folded into a slot shape. There are four slots at the bottom of the implant, designed to bring the spinal roots (perhaps two anterior and two posterior ones) into close apposition with the electrodes. Such top placement of a neural interface is rather unusual as existing spinal root electrodes (e.g. Finetech-Brindley stimulators) have employed the cuff design. In order to be able to record neural activity and efficiently deliver the electrical current, the slots must be well-matched in size to the diameter of spinal roots. The initial application for the Active Book implant would be the control of bladder voiding in spinal cord injury. The effectiveness of the prosthetic bladder voiding will be similarly limited as in other sacral root stimulators, including the sensory perception of stimulation in people with residual below-injury sensation and concomitant activation of the bladder and urethral sphincter muscles, as well as other pelvic floor muscles. Other applications in paralyzed humans, such as the control of arm or leg muscles, are not unlikely to be successful with this implant as the applied surface stimulation would not be able to selectively activate a specific arm/leg muscle. Such lack of selectivity is inherent to the anatomy of the anterior spinal roots, which are comprised of mixed axonal bundles innervating different, sometimes antagonistic, muscles.
A remarkable milestone has been reached in the resolution of retinal implants – a whopping 1520 pixels! In addition to vision restoration, the implant provides a first-ever vision-enhancing capability – the sensitivity to near-infrared light.
A remarkable milestone has been reached in the resolution of retinal implants – a whopping 1520 pixels (38×40)! Following on the heels of a recent success of Argus II retinal implants developed by the Second Sight, this implant by the German Retina Implant AG brings a 25-fold increase in resolution and several other unique features. Its subretinal placement is closer to the retinal pigment epithelium than can be achieved with epiretinal placement. This provides more selective stimulation of photoreceptors and results in further improvement in the implant’s resolution. The light sensing circuitry (silicon photodiodes) is built into the implant allowing it to move along with the eye movements. This is beneficial for more natural cortical processing of visual information, as the visual map in the visual is adjusted during each saccade. Other types of retinal implants use an external videocamera (usually mounted on the glasses) that does not adjust the video information during the eye movements. The implant is 3 x 4 mm and 50 µm thick. In addition to vision restoration, the implant provides a first-ever vision-enhancing capability – the sensitivity to near-infrared light. Extending the spectrum of perceived light can have some interesting implications, such as the ability to see a thermal shape of the object (the black body radiation) even in complete darkness. The ongoing research by Prof. Eberhart Zrenner at the University of Tuebingen aims to evaluate these implants to develop strategies for further improvements in the sensitivity and targeting of the implants. According to the paper published in the November issue of Proceedings of Royal Society B, the implants have been tested in three patients with hereditary retinal degeneration. All patients could locate bright objects on a dark table, and one patient discerned shades of grey with only 15% contrast. An important question for the retinal implant community, so far not answered by the study, is: how many pixels in the implant provide truly unique information to the retina and whether this spatial threshold has been reached with a 70-µm spacing used in the implant. The answer to this question has far-reaching implications for further technology developments: 1) whether further improvements in the density of planar arrays will translate into more focal stimulation and 2) whether the stimulating sites should be microfabricated to extend from the chip toward the retina in order to achieve the intended 70-µm spatial resolution.
Cochlear implants have been around for decades restoring hearing in profoundly deaf people. Now, with the help of Jay Rubinstein, James Phillips, and other scientists at University of Washington, the old “dog” from Cochlear Ltd has learned a new trick: restoring the sense of balance. The Nucleus® cochlear implant was modified to include three leads with multiples stimulation sites. The leads are implanted into all three semicircular canals of the inner ear to restore the 3D rotational information. The details of the implant design and surgery are provided in this video.