In March 2016, DARPA announced the Targeted Neuroplasticity Training (TNT) program, an effort to enlist the body's peripheral nervous system to achieve something that has long been considered the brain's domain alone: facilitation of learning. Work on TNT has now begun.

The crux of the wide-ranging program is to identify optimal and safe neurostimulation methods for activating "synaptic plasticity"-a natural process in the brain, pivotal to learning, that involves the strengthening or weakening of the junctions between two neurons-then build those methods into enhanced training regimens that accelerate the acquisition of cognitive skills.

TNT was inspired by recent research showing that stimulation of certain peripheral nerves can activate regions of the brain involved with learning. Such signals can potentially trigger synaptic plasticity by releasing neurochemicals that reorganize neural connections in response to specific experiences.

TNT researchers will strive to identify the physiological mechanisms that might allow this natural process to be enhanced using electrical stimulation of peripheral nerves, making the brain more adaptive during key points in the learning process.

"DARPA is approaching the study of synaptic plasticity from multiple angles to determine whether there are safe and responsible ways to enhance learning and accelerate training for skills relevant to national security missions," said Doug Weber, the TNT Program Manager.

DARPA is funding eight efforts at seven institutions in a coordinated research program that focuses initially on the fundamental science of brain plasticity and aims to conclude with human trials in healthy volunteers.

To facilitate transition into real-world applications, some of the teams will work with intelligence analysts and foreign language specialists to understand how they train currently so that the TNT platform might be refined around their needs. The program will also compare the efficacy of invasive (via an implanted device) versus non-invasive stimulation, investigate how to avoid potential risks and side effects of stimulation, and hold a workshop on the ethics of using neurostimulation to enhance learning.

The first half of the TNT program focuses on deciphering the neural mechanisms underlying the influence of nerve stimulation on brain plasticity; discovering physiological indicators that can verify when stimulation is working effectively; and identifying and mitigating any potential side effects of nerve stimulation.

The second half of the program will focus on using the technology in a variety of training exercises to measure improvements in the rate and extent of learning.

The institutions listed below are leading teams exploring aspects of using stimulation to activate plasticity.

+ An Arizona State University team led by Dr. Stephen Helms Tillery is targeting stimulation of the trigeminal nerve to promote synaptic plasticity in the sensorimotor and visual systems of the brain. Through partnerships with the Air Force Research Laboratory, the U.S. Air Force's 711th Human Performance Wing, and the U.S. Army Research Institute of Environmental Medicine, the team will evaluate TNT stimulation protocols with two groups of volunteers-one studying intelligence, surveillance, and reconnaissance, and another practicing marksmanship and decision-making.

+ A Johns Hopkins University team led by Dr. Xiaoqin Wang is focusing on regions of the brain involved in speech and hearing to understand the effects of plasticity on language learning. The team will compare the efficacy of invasive versus non-invasive vagal nerve stimulation (VNS), testing the ability of volunteers to discriminate phonemes, learn words and grammar, and produce the unique sounds demanded by some foreign languages.

+ In one of two efforts DARPA is funding at the University of Florida, a team led by Dr. Kevin Otto is identifying which neural pathways in the brain VNS activates. The team will also conduct behavioral studies in rodents to determine the impact of VNS on perception, executive function, decision-making, and spatial navigation.

+ In the second University of Florida effort, a team led by Dr. Karim Oweiss will use an all-optical approach combining fluorescent imaging and optogenetics to interrogate the neural circuity that connects neuromodulatory centers in the deep brain to decision-making regions in the prefrontal cortex, and optimize VNS parameters around this circuitry to accelerate learning of auditory discrimination tasks by rodents.

+ A University of Maryland effort led by Dr. Henk Haarmann is studying the impact of VNS on foreign language learning. His team will use electroencephalography (EEG) to examine the effects of VNS on neural function during speech perception, vocabulary, and grammar training.

+ A University of Texas at Dallas team led by Dr. Mike Kilgard is identifying optimal stimulation parameters to maximize plasticity, and comparing the effects of invasive versus non-invasive stimulation in individuals with tinnitus as they perform complex skill-learning tasks such as acquiring a foreign language. The team will also investigate the longevity of stimulation effects to determine if follow-up training is needed for long-term retention of learned skills.

+ A University of Wisconsin team led by Dr. Justin Williams is using state-of-the-art optical imaging, electrophysiology, and neurochemical sensing techniques in animal models to measure the influence of vagal and trigeminal nerve stimulation on boosting activity of neuromodulatory neurons in the brain.

+ A Wright State University team led by Dr. Timothy Broderick is focusing on identifying epigenetic markers of neuroplasticity and indicators of an individual's response to VNS. Through a partnership with the Air Force Research Laboratory and the U.S. Air Force's 711th Human Performance Wing, the team will also work with volunteer intelligence analyst trainees studying object and threat recognition to determine the impact of non-invasive VNS on that training.

DARPA will support a future regulatory science effort within the U.S. Food and Drug Administration (FDA), which approved VNS for the treatment of epilepsy and depression. FDA scientists, led by Dr. Srikanth Vasudevan, will further explore the safety and efficacy of VNS in an animal model, including an examination of any role the sex of the animal may have on potential effects of chronic use of VNS.

DARPA's TNT efforts differ from the Agency's previous neuroscience and neurotechnology endeavors by seeking not to restore lost function but to advance capabilities in healthy individuals.

By the end of the planned four-year program, DARPA aims to demonstrate that TNT methods and technologies can yield at least a 30 percent improvement in learning rate and/or skill performance over traditional training regimens, with minimal negative side effects.

"The Defense Department operates in a complex, interconnected world in which human skills such as communication and analysis are vital, and the Department has long pushed the frontiers of training to maximize those skills," Weber said.

"DARPA's goal with TNT is to further enhance the most effective existing training methods so the men and women of our Armed Forces can operate at their full potential."

Recognizing that these new technologies for learning and training could raise social and ethical issues, the TNT program is funding Arizona State University to host a national ethics workshop within the first year of the program.

The workshop will engage scientists, bioethicists, regulators, military specialists, and others in discussion of those issues, and will produce for wider consideration a report on potential ethical issues relating to cognitive enhancement for warfighters.

TNT is a fundamental research effort. Teams performing the research are encouraged to publish their findings in peer-reviewed journals.

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