Hassan, U. | bioRxiv Science

bioRxiv2023

Auditory confounds can drive online effects of transcranial ultrasonic stimulation in humans

Transcranial ultrasonic stimulation (TUS) is rapidly emerging as a promising non-invasive neuromodulation technique. TUS is already well-established in animal models, providing foundations to now optimize neuromodulatory efficacy for human applications. Across multiple studies, one promising protocol, pulsed at 1000 Hz, has consistently resulted in motor cortical inhibition in humans (Fomenko et al., 2020). At the same time, a parallel research line has highlighted the potentially confounding influence of peripheral auditory stimulation arising from TUS pulsing at audible frequencies. In this study, we disentangle direct neuromodulatory and indirect auditory contributions to motor inhibitory effects of TUS. To this end, we include tightly matched control conditions across four experiments, one preregistered, conducted independently at three institutions. We employed a combined transcranial ultrasonic and magnetic stimulation paradigm, where TMS-elicited motor-evoked potentials (MEPs) served as an index of corticospinal excitability. First, we replicated motor inhibitory effects of TUS but showed through both tight controls and manipulation of stimulation intensity, duration, and auditory masking conditions that this inhibition was driven by peripheral auditory stimulation, not direct neuromodulation. Further, we consider neuromodulation beyond driving overall excitation/inhibition and show preliminary evidence of how TUS might interact with ongoing neural dynamics instead. Primarily, this study highlights the substantial shortcomings in accounting for the auditory confound in prior TUS-TMS work where only a flip-over sham and no active control was used. The field must critically reevaluate previous findings given the demonstrated impact of peripheral confounds. Further, rigorous experimental design via (in)active control conditions is required to make substantiated claims in future TUS studies. Only when direct effects are disentangled from those driven by peripheral confounds can TUS fully realize its potential for research and clinical applications.

neuroscience↗

bioRxiv2022

Automated real-time EEG sleep spindle detection for brain state-dependent brain stimulation

Sleep spindles are a hallmark electroencephalographic (EEG) feature of non-rapid eye movement (NREM) sleep and believed to be instrumental for sleep-dependent memory reactivation and consolidation. However, direct proof of their causal relevance is hard to obtain, and our understanding of their immediate neurophysiological consequences is limited. To investigate their causal role, spindles need to be targeted in real-time with sensory or non-invasive brain stimulation techniques. While fully automated offline detection algorithms are well established, spindle detection in real time is highly challenging due to their spontaneous and transient nature. Here, we present the real-time spindle detector (RTSD), a robust multi-channel EEG signal processing algorithm that enables the automated triggering of stimulation during sleep spindles in a phase-specific manner. We validated the RTSD method by streaming pre-recorded sleep EEG datasets to a real-time computer system running a Simulink(R) Real-Time implementation of the algorithm. Sleep spindles were detected with high levels of sensitivity ([~]83%) and precision ([~]78%) and an F1-score of [~]0.81 in reference to state-of-the-art offline algorithms (which reached similar levels when compared to each other), for both naps and full nights, and largely independent of sleep scoring information. Detected spindles were comparable in frequency, duration, amplitude, and symmetry, and showed the typical time-frequency characteristics as well as a centroparietal topography. Spindles were detected close to their center and reliably at the predefined target phase. The RTSD algorithm therefore empowers researchers to target spindles during human sleep and apply the stimulation method and experimental paradigm of their choice.

neuroscience↗