Ionic Direct Current for Cortical Network Gain Modulation

Neural population gain is a critical parameter in brain computation, influencing processes such as attention, learning, sensory adaptation, and decision-making. Despite its importance, existing neuromodulation technologies lack the temporal (milliseconds) and spatial (200 µm) precision needed to dynamically and locally modulate gain, creating a significant gap in our ability to study and manipulate neural circuits. This proposal addresses this gap by developing and refining ionic direct current (iDC) stimulation as a novel neuromodulation tool. Unlike existing methods such as optogenetics or drugs, iDC enables high-precision modulation of neural population gain while preserving natural activity, offering unparalleled potential for investigating and manipulating brain function. Our overarching goal is to optimize iDC for targeted modulation of neural population gain at the scale of cortical columns. To achieve this, we propose three independent but complementary aims. Aim 1 will develop computational models to predict the effects of iDC parameters (source locations, polarity, and relative amplitudes) on neural population gain. By integrating multiple biophysical assumptions within a 200 µm scale, these models will provide testable predictions to guide experimental designs. Aim 2 will experimentally validate iDC's ability to modulate gain, first in the anesthetized rat somatosensory cortex (Aim 2.1) and then in a behavioral model of tactile hypersensitivity using Shank3-/- mice (Aim 2.2). These experiments will explore iDC’s capacity to reduce cortical gain and alleviate behavioral deficits linked to excitatory-inhibitory imbalances. Aim 3 focuses on engineering a multichannel wireless iDC backpack system for chronic, multi-site gain modulation studies in rodents, enabling widespread adoption of this technology. Our innovative approach integrates computational modeling, experimental neuroscience, and cutting- edge engineering to develop a transformative tool for neuroscience research. This work has the potential to uncover causal links between neural population gain and behavior, advance our understanding of brain computation, and create new therapeutic avenues for gain-related disorders. Project Number: 1R01NS146406-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Gene Fridman (+1 co-PI) | Institution: JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD | Award Amount: $580,924 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 NINC-Q (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11275715