Methods by which to achieve non-invasive deep brain stimulation via temporally interfering with electric fields have been proposed, but the precision of the positioning of the stimulation and the reliability and stability of the outputs require improvement. In this study, a temporally interfering electrical stimulator was developed based on a neuromodulation technique using the interference modulation waveform produced by several high-frequency electrical stimuli to treat neurodegenerative diseases. The device and auxiliary software constitute a non-invasive neuromodulation system. The technical problems related to the multichannel high-precision output of the device were solved by an analog phase accumulator and a special driving circuit to reduce crosstalk. The function of measuring bioimpedance in real time was integrated into the stimulator to improve effectiveness. Finite element simulation and phantom measurements were performed to find the functional relations among the target coordinates, current ratio, and electrode position in the simplified model. Then, an appropriate approach was proposed to find electrode configurations for desired target locations in a detailed and realistic mouse model. A mouse validation experiment was carried out under the guidance of a simulation, and the reliability and positioning accuracy of temporally interfering electric stimulators were verified. Stimulator improvement and precision positioning solutions promise opportunities for further studies of temporally interfering electrical stimulation.

Mismatch negativity (MMN) is suitable for studies of preattentive auditory discriminability and the auditory memory trace. Subjective cognitive decline (SCD) is an ideal target for early therapeutic intervention because SCD occurs at preclinical stages many years before the onset of Alzheimer’s disease (AD). According to a novel lifespan-based model of dementia risk, hearing loss is considered the greatest potentially modifiable risk factor of dementia among nine health and lifestyle factors, and hearing impairment is associated with cognitive decline. Therefore, we propose a neurofeedback training based on MMN, which is an objective index of auditory discriminability, to regulate sensory ability and memory as a non-pharmacological intervention (NPI) in SCD patients. Seventeen subjects meeting the standardized clinical evaluations for SCD received neurofeedback training. The auditory frequency discrimination test, the visual digital N-back (1-, 2-, and 3-back), auditory digital N-back (1-, 2-, and 3-back), and auditory tone N-back (1-, 2-, and 3-back) tasks were used pre- and post-training in all SCD patients. The intervention schedule comprised five 60-min training sessions over 2 weeks. The results indicate that the subjects who received neurofeedback training had successfully improved the amplitude of MMN at the parietal electrode (Pz). A slight decrease in the threshold of auditory frequency discrimination was observed after neurofeedback training. Notably, after neurofeedback training, the working memory (WM) performance was significantly enhanced in the auditory tone 3-back test. Moreover, improvements in the accuracy of all WM tests relative to the baseline were observed, although the changes were not significant. To the best of our knowledge, our preliminary study is the first to investigate the effects of MMN neurofeedback training on WM in SCD patients, and our results suggest that MMN neurofeedback may represent an effective treatment for intervention in SCD patients and the elderly with aging memory decline.

Neurofeedback targets self-regularized brain activity to normalized brain function based on brain-computer interface (BCI) technology. Although BCI software or platforms have continued to mature in other fields, little effort has been expended on neurofeedback applications. Hence, we present BrainKilter, a real-time electroencephalogram (EEG) analysis platform based on a ''4-tier layered model''. The purposes of BrainKilter are to improve portability and accessibility, allowing different users to choose various options to perform EEG processing, target stimulation-induction through a pipeline, and analyze data online, essentially, to design a protocol paradigm and applicable BCI technology for neurofeedback experiments. The data processing effectiveness and application value of BrainKilter were tested using multiple-parameter neurofeedback training, in which BrainKilter regulated the amplitude of mismatch negative (MMN) signals for healthy individuals. The proposed platform consists of a set of software modules for online protocol design and signal decoding that can be conveniently and efficiently integrated for neurofeedback design and training. The BrainKilter platform provides a truly easy-to-use environment for customizing the experimental paradigm and for optimizing the parameters of neurofeedback experiments for research and clinical neurofeedback applications using BCI technology. INDEX TERMS BrainKilter, BCI, MMN, neurofeedback, platform, real-time.

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