The United States military has a long tradition of driving technological innovation and the field of neurotechnology is no exception. The U.S. Defense Advanced Research Projects Agency (DARPA) has several neurotechnology initiatives underway headed by Dr. Justin Sanchez. Two of these programs specifically focus on the applications of invasive brain stimulation. Systems-based neurotechnology for emerging therapies (SUBNETS) seeks to develop technological solutions to treat neuropsychiatric illness, notably post-traumatic stress disorder (PTSD), when psychotherapy and pharmaceutical interventions are ineffective . Restoring active memory (RAM) aims to develop neurotechnology to mitigate the debilitating memory loss associated with traumatic brain injury, which has affected over 270 000 American service members since 2000. Both of these programs are part of the broader presidential Brain Research through Advancing Innovative Neurotechnologies® BRAIN Initiative (https://www.braininitiative.nih.gov/). In addition, efforts have been focused on mitigating the effects of sleep deprivation, increasing training efficiency, and even boosting decision making skills .
History of Electrical Brain Stimulation
The scientific discovery that brain function is driven by electrical impulses came about in the early 1800s when a scientist name Giovanni Aldini found himself locked in a debate with the physicist Alessandro Volta about the nature of nerve function. This debate led Aldini to build on the work of bioelectromagnetics pioneer Luigi Galvani in order to carry out the earliest known electrical brain stimulation experiments in the hopes of achieving re-animation. It should come as no surprise that Marie Shelley’s Frankenstein was written during this time period. Aldini’s attempts at reanimation were ultimately unsuccessful, but he went on to experiment with electrical shock as a potential cure for various psychiatric conditions . This early experimentation laid the groundwork for the modern fields of electro convulsive therapy (ECT) and magnetic seizure therapy (MST), and the less invasive transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS).
While these techniques are certainly invasive in a colloquial sense, they are still considered non-invasive in a medical sense. Invasive brain stimulation traditionally involves implanting electrodes directly into the brain in order to stimulate neuronal function. The first invasive brain stimulation experiments were conducted in rats by Olds and Milner in the 1950s . In these experiments they found that stimulating the regions of the brain that were responsive to reward caused rats to behave in a manner consistent with receiving a reward. This was the first evidence that electricity delivered directly to the brain could be used to modify behavior . This work was then extended by Jose Delgado in the 1960s. Delgado theorized that implanted electrical stimulation could control all kinds of behavior, and not just in rats. He chose to test this hypothesis by attempting to curb aggression in raging bulls. This experimentation continued into the late 1970s in various animal models (including primates), but did not progress to human trials .
Modern Day Electrical Brain Stimulation
Nevertheless, the idea of using implanted electrodes to modify brain function in humans did not end there. Concurrent with Delgado’s work, Medtronic developed the first “neural pacemaker,” which was first used by Hosobuchi et al. in 1973 to treat chronic pain by stimulating the thalamus . This technique came to be called deep brain stimulation (DBS). However, this application of DBS was never approved by the FDA. It was not until 1997 that DBS was approved as a treatment for the tremors characteristic of Parkinson’s disease. Clinical development efforts are currently underway for numerous conditions including chronic pain, major depression, obsessive compulsive disorder, and post traumatic stress disorder .
According the statistics released by the U.S. Veterans Association, PTSD affects 30% of U.S. veterans, and treatment of PTSD relies heavily on compliance with psychotherapy and medications such as selective serotonin reuptake inhibitors (SSRIs) and antimanic agents like lithium . However, medication compliance is often low, which can hinder recovery. Additionally, PTSD is often comorbid with other mental health problems including substance abuse . This can further decrease compliance, especially in cases where all other interventions are ineffective. In these cases, DBS may provide an alternative course of treatment, helping those who suffer from PTSD alleviate their symptoms without the overhead of taking daily medication. One of the DBS protocols being investigated for PTSD treatment involves drilling two small holes in the skull, and implanting very thin electrodes (approximately 1.27 mm) into the amygdala on both sides of the brain. This is the region of the brain that, among other things, mediates the emotional strength of memories and is known to be overly active in those who suffer from PTSD. In 2015, following several years of animal trials, DBS was successfully used to help manage the symptoms of treatment-resistant PTSD in a human. The person who underwent the procedure reports that they have experienced a marked decline in the severity of nightmares that were previously preventing them from sleeping more than a few hours per night . A clinical trial. headed by doctors Langevin and Koek is currently underway to determine the effectiveness of this treatment in the broader population .
Memory problems also have debilitating effects on veterans suffering from TBI . The RAM program was created by DARPA with a goal of developing an implantable device that can be used to treat memory problems in patients with TBI. One of teams funded by this initiative is led by Drs. Michael Kahana and Daniel Rizzuto at the University of Pennsylvania (http://memory.psych.upenn.edu/RAM). Their lab studies human memory using a variety of techniques, including closed-loop brain stimulation. As part of the RAM effort Rizzuto’s lab has created an open database of the brain signals associated with memory tasks. So far, all of the recordings have been done in patients with epilepsy who already have both recording and stimulating electrodes implanted for the purpose of mapping brain function prior to brain resection surgery. In order to identify the neural correlates of memory, Rizzuto and his team had participants perform free recall tasks – for example, looking at a list of words and asking them to remember as many as possible. These tasks were performed for an hour at a time, sometimes several times per day. By analyzing the data from the recording electrodes, Rizzuto’s lab was able to predict which words would be remembered and which would be forgotten.
Additionally, by applying electrical stimulation at specific times, they were able to increase the percentage of recalled words. This is now being refined into a closed loop brain computer interface system where brain stimulation is applied whenever the system detects that the recorded activity looks more like a word that will be forgotten than one that will be remembered. As part of the RAM program Medtronic has been developing a low-latency, closed-loop stimulation system that is capable of precisely stimulating the memory circuits of the brain. The first subject data using this device is scheduled to be collected in February of this year.
Electrical brain stimulation has limitations. In certain cases stimulating electrodes affect not only the cells in the region where they were implanted, but cause electrical stimulation to spread through the fiber pathways to other brain regions as well. Depending on where electrodes are implanted and their specific use case, this spread has the potential to cause unwanted short and long term side effects. Optogenetics, an emerging field of research that uses light to stimulate neurons that have been modified to express light sensitive genes, may someday provide a way to circumvent these limitations. In rats, researchers were able to selectively inhibit fear responses by shining light on neurons in the basal amygdala – the same region that is being investigated as a target for electrical stimulation . However, optogenetics relies on the ability to make specific cells sensitive to light. Clinical trials for this technique are currently underway to evaluate the safety and effectiveness of optogenetics to treat a variety of conditions, including certain types of blindness and chronic pain .
These advances in medical technology are inextricably linked to discussions of human augmentation, especially in the context of military research. However, the existence of “super-soldiers” enhanced by brain implants are far from a reality. Although a great deal of progress has been made in animal models towards aims such as accelerated learning and increased memory capacity using implantable brain technology, research in humans is currently limited to therapeutic applications. Even if the therapeutic applications were to augment function beyond current human capabilities, it is still an open question whether or not the risks would be deemed acceptable for non-clinical populations. The only precedent for cognitive enhancement comes from pharmaceuticals, which are often used to keep soldiers alert. Similarly, non-invasive brain stimulation (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) techniques are being investigated for accelerated learning, improved decision making, and alertness. However, unlike an implanted device, these substances and techniques can be used on a per-need basis. While they do carry risks, both long and short term, their use can be discontinued once they are no longer needed. A brain implant, although considered reversible, carries the risks of surgery at both implantation and at removal, and cannot be replaced or repaired outside of a hospital.
Implantable neurotechnology carries a great deal of therapeutic potential. Someday, it may even hold the potential to enhance humans beyond their natural capabilities. However, behind each clinical trial are decades of basic research. This research is essential for neuroscientists to better understand brain function, and for engineers to design better materials, algorithms, and software. In addition, each technological advance raises new ethical questions about the future of psychiatric care, the accessibility of these treatments, and their potential harms. It is imperative that researchers, physicians, patients, and politicians alike continue to have an open dialogue about the future of implantable brain technology in order to ensure that these advances continue to benefit those who most need the treatments.
Melanie Segado is co-founder and science director of NeuroTechX. She is currently pursuing a degree in cognitive neuroscience at McGill University.