Intracortical Recording Interfaces: Current Challenges to Chronic Recording Function Bhagya Gunasekera, † Tarun Saxena, ‡ Ravi Bellamkonda, ‡ and Lohitash Karumbaiah* ,† † Regenerative Bioscience Center, ADS Complex, The University of Georgia, Athens, Georgia 30602-2771, United States ‡ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332-0535, United States ABSTRACT: Brain Computer Interfaces (BCIs) offer signifi- cant hope to tetraplegic and paraplegic individuals. This technology relies on extracting and translating motor intent to facilitate control of a computer cursor or to enable fine control of an external assistive device such as a prosthetic limb. Intracortical recording interfaces (IRIs) are critical components of BCIs and consist of arrays of penetrating electrodes that are implanted into the motor cortex of the brain. These multielectrode arrays (MEAs) are responsible for recording and conducting neural signals from local ensembles of neurons in the motor cortex with the high speed and spatiotemporal resolution that is required for exercising control of external assistive prostheses. Recent design and technological innovations in the field have led to significant improvements in BCI function. However, long-term (chronic) BCI function is severely compromised by short-term (acute) IRI recording failure. In this review, we will discuss the design and function of current IRIs. We will also review a host of recent advances that contribute significantly to our overall understanding of the cellular and molecular events that lead to acute recording failure of these invasive implants. We will also present recent improvements to IRI design and provide insights into the futuristic design of more chronically functional IRIs. KEYWORDS: Brain computer interfaces, intracortical neural interfaces, foreign body response ■ THE NEED FOR BRAIN COMPUTER INTERFACES Spinal cord injuries (SCI) and neurodegenerative diseases often lead to severe neurological impairment and permanent incapacitation of individuals that suffer them. Common outcomes include paraplegia, which affects the lower extremities, or tetraplegia, which affects the limbs and torso. In addition to physical incapacitation, the situation is also financially and psychologically burdensome to the individuals, their families, and caregivers. According to The National SCI Statistical Center, around 276 000 people live with SCI in the United States. 1 Around 12 500 new patients suffer SCI in the country each year, with the annual recurring cost ranging from $41 554 for incomplete motor function to $182 033 for high tetraplegia, and estimated lifetime costs ranging from $1 096 770 to $4 651 158. A number of methods are being used to treat and rehabilitate patients suffering from SCI. Aggressive physiotherapy is a foremost consideration, and has demonstrated considerable success in returning the ability to walk. 2,3 A number of pharmacological interventions such as methylprednisolone have also gained attention over the years, but continue to be the subject of debate for SCI related intervention. 4,5 Immune suppressors such as rapamycin have been used in attempts to mitigate SCI related neural tissue damage in mouse models. 6 Peripheral nerve grafts have shown to promote central nervous system (CNS) axon regeneration, 7 and fetal spinal cord grafts have been used to support regrowth of host axons. 8 More recently, autologous olfactory ensheathing cell transplantation conducted in phase 1 clinical trials have shown promising results in regenerating lesioned axons. 9 Stem cell therapies involving the use of embryonic stem cells, mesenchymal stem cells, neural stem/progenitor cells, and induced pluripotent stem cell transplants have been considered for regenerative therapy of the injured spinal cord. 10-13 Electrical stimulation (ES) of motor neurons has also shown promise in the rehabilitation of patients who have experienced SCI. Intact motor neurons, when electrically stimulated, have been demonstrated to help train paralyzed muscles, reduce muscular atrophy, and improve cardiovascular strength. 14 However, in spite of recent advances, much work remains to be done to achieve the ultimate goal of returning volitional movement to individuals suffering from long-term tetraplegia or paraplegia. Recently, alternative approaches such as the use of BCIs are being increasingly considered to help return volitional move- ment to paraplegic or tetraplegic patients. BCIs typically consist of a neural interface (NI), which is capable of recording neural signals from the brain and transmitting them to a computer. The acquired neural signals are subsequently digitized and Special Issue: Monitoring Molecules in Neuroscience 2014 Received: November 8, 2014 Revised: January 5, 2015 Review pubs.acs.org/chemneuro © XXXX American Chemical Society A DOI: 10.1021/cn5002864 ACS Chem. Neurosci. XXXX, XXX, XXX-XXX