An implantable piezoelectric ultrasound stimulator (ImPULS) for deep brain activation

Abstract

Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO 3 ]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.

Abstract via europepmc.

Flags from extraction

• n_subjects — Sample sizes are reported per sub-experiment (e.g., N=3 mice for 500 kHz dCA1 condition, N=3 for 500 kHz 10% duty factor, 3 mice/group for SNc stimulation, 4 mice in a supplementary 1.5 s SNc trial, unspecified counts for ex vivo slice and chronic experiments) rather than as a single total exposed to ultrasound; not aggregated here to avoid double-counting or inaccuracy.
• exposures[0].free_field.pressure_kpa — The 100 kPa focal pressure is the paper's headline device characterization (FEA-simulated maximum adjacent to the transducer; 59.2 kPa was separately measured at 15 micrometers) using a 20 V(p-p) drive signal during bench characterization, whereas the ex vivo/in vivo neurostimulation experiments used 10 V(p-p); the pressure actually delivered during stimulation may differ from this reported figure.
• exposures[1].free_field.pressure_kpa — Same 100 kPa device characterization caveat as exposures[0]: measured/simulated at 20 V(p-p), while in vivo dCA1 stimulation used 10 V(p-p).
• exposures[1].timing.pulse_repetition_frequency_hz — A PRF of 1.5 kHz is explicitly stated only for the 50%-duty-cycle chronic dCA1 condition; it is not restated for the acute 10% duty factor condition shown in Fig. 3, though the same value may apply.
• exposures[2].free_field.pressure_kpa — No pressure value is stated in the text specifically for the 514 kHz device used in SNc stimulation.
• direction_of_effect — SNc stimulation produced dopamine release increases in most animals but a decrease in at least one case; authors speculate this reflects co-stimulation of inhibitory SNr neurons rather than a parameter-dependent effect.