Neuromodulation Mechanism and Parameter Design

Axis 1 primary, Axis 2 secondary. The lab's central forward-translation thrust, addressing the cellular and circuit mechanisms underlying intracortical microstimulation, focused ultrasound, low-intensity pulsed ultrasound, and other neuromodulation modalities, with direct application to BCI sensory restoration, deep brain stimulation, and emerging non-invasive neuromodulation therapies.

Open Scientific Question

How do parametric stimulation patterns produce specific subjective experiences (touch, vision, proprioception) and specific therapeutic effects, and what stimulation parameters maximize the desired neural and behavioral response while minimizing tissue damage and perceptual fading? This is the central forward-translation question of the field, the answer to which determines whether sensory restoration through ICMS, DBS for depression and PTSD, focused ultrasound neuromodulation, and emerging closed-loop systems will succeed clinically. The lab's distinctive contribution is to use the cellular and vascular mechanism developed in Axis 2 to inform parameter design, rather than treating the brain as a black box to be optimized empirically.

Anchor Papers from the Lab

•         Hughes CL, Chen K, Grill WM, Kozai TDY. Neural mechanisms underlying intracortical microstimulation for sensory restoration  Nature Biomedical Engineering, 2026. Mechanistic framework for ICMS-driven cortical activation with stimulation parameter recommendations for sensory restoration in cortical neuroprosthetics.

•         Kozai TDY et al. Solving the problem of inception, perspective on cross-species translation of intracortical microstimulation. Journal of Neural Engineering, 2026. The Parallel Translation framework, with 16 co-authors across bioengineering, neurobiology, computational neuroscience, neuroethics, philosophy, ophthalmology, rehabilitation medicine, and English.

•         Hughes CL, Kozai TDY. Dynamic amplitude modulation of microstimulation evokes biomimetic onset and offset transients. Brain Stimulation, 2023, 16, 939-965. Biomimetic stimulation extending perceptual duration, with mechanism for the biomimetic effect.

•         Stieger KC, Eles JR, Ludwig KA, Kozai TDY. In vivo microstimulation with cathodic and anodic asymmetric waveforms modulates spatiotemporal calcium dynamics in cortical neurons. Journal of Neural Engineering, 2022. Parametric stimulation effects on calcium dynamics across cortical neuron populations.

•         Hughes CL, Stieger KC, Chen K, Vazquez AL, Kozai TDY. Spatiotemporal properties of cortical excitatory and inhibitory neuron activation by sustained and bursting electrical microstimulation. iScience, 2025, 28(6). Cell-type-specific responses to sustained ICMS.

•         Eles JR, Stieger KC, Kozai TDY. The temporal pattern of intracortical microstimulation pulses elicits distinct temporal and spatial recruitment of cortical pyramidal cells. Journal of Neural Engineering, 2021, 18(1). Resolution of the 30-year question on perceptual fading by identifying neurovascular and metabolic constraints as the dominant failure mode, with concurrent identification of inhibitory interneuron recruitment as a parallel mechanism.

•         Stocking KC, Vazquez AL, Kozai TDY. Intracortical neural stimulation with untethered, ultrasmall carbon fiber electrodes mediated by the photoelectric effect. IEEE Transactions on Biomedical Engineering, 2019, 66, 2402-2412. Photoelectric stimulation through ultrasmall electrodes.

Disease and Translational Connections

•         Sensory restoration in cortical neuroprosthetics. Direct forward translation to the Pitt human BCI program (Drs. Collinger and Gaunt) and to industry partners working on tactile and visual sensory restoration.

•         Focused ultrasound and microbubble-mediated neuromodulation. A non-invasive perturbation modality with translational application in stroke, MS, and AD.

•         LIPUS for non-invasive cellular perturbation. Industry collaboration with Actuated Medical, with Nature Communications 2024 demonstration of microglial modulation.

Skills Developed by Trainees on This Thrust

•         Parametric ICMS design across current, frequency, pulse width, duty cycle, and waveform shape

•         Focused ultrasound with microbubbles, low-intensity pulsed ultrasound, and emerging non-invasive neuromodulation modalities

•         Cell-type-specific calcium imaging during stimulation, with spatiotemporal analysis pipelines

•         Biophysical modeling of stimulation field spread and cellular response

•         Behavioral and psychophysical readouts in rodent and (through collaborations) NHP and human preparations

•         Direct industry-relevant analytical pipelines for sensory restoration and clinical neuromodulation