Objective. Upcoming neuroscientific research will depend significantly on tools enabling bidirectional and context dependent interaction with nervous tissue, whether through invasive or non-invasive means, targeting specific neural regions, the entire brain, or functional networks. To facilitate the associated future neuroscientific discoveries we have created HarPULL, a genuinely real-time system that tracks oscillatory brain state and can be coupled with a range of feedback and stimulation devices to close the interactive loop in a precise and brain state dependent manner. Approach. The HarPULL technology ensures reliable and accurate real-time phase tracking based on the framework of the state-space estimation techniques operationalized by Kalman filtering for optimal tracking of the complex valued analytic signal associated with the target brain rhythm. To avoid data transfer delays and to obtain a truly real-time system the algorithm is implemented on the computational core of an EEG amplifier controlled by a real-time operation system. Real and imaginary parts of the analytic signal furnish direct access to the instantaneous phase and amplitude of the brain rhythm. Systems performance is tested with simulated and real data both online and offline as well as within a real-time state dependent TMS using a phantom and human subjects. Main results. We augment the existing literature by inscribing the steady-state Kalman filters into the oscillatory brain state estimation framework. We also show that taking into account the 1/f nature of the brain noise and the use of the steady state colored Kalman filter further improves phase tracking performance in both simulated and real data. We implement our real-time phase tracking algorithms on board of an EEG device and use it to trigger the TMS device contingent upon the target phase. We demonstrate minimal delay (2 ms) between the occurrence of the predetermined rhythm phase in the cortex and the corresponding magnetic stimulus. Also, using this setup in a real-time setting we observe a significant modulation of the motor evoked potentials (MEP) by the sensorimotor rhythm phase. Finally, using our HarPULL technology, for the first time in real-time we obtain muscle cortical representation (MCR) maps for different target phase values. The acquired MCRs appear to be clearly dependent on the phase value. TMS during the excitation state consistently producing nearly 50% greater MEP amplitudes over the entire map as compared to the inhibitory state responses. We have also observed better delineation between the representations of several muscles when the stimulation is performed in the excitation state. Significance. HarPULL is the first technology for the instantaneous tracking of the brain rhythmic activity and operating exclusively on the truly real-time computational core furnished by a digital EEG device. The algorithmic core capable of tracking both phase and the instantaneous rhythm power boosts specificity of the associated magnetic stimulation and potentially other forms of brain-state contingent feedback signals. Our technological solution establishes a real-time nearly instantaneous non-invasive contact with a living brain which has a broad range of clinical and scientific applications.

The authors have declared no competing interest.

The research leading to these results has received funding from the Basic Research Program at the National Research University Higher School of Economics.

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Ethics committee/IRB of HSE University gave ethical approval for this work

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