Research On Development Of Ultrasonic Transducers And Brain Stimulation For Pain Inhibition

Chronic pain is one of the most common health care problems in the world today,which negatively impacts people’s quality of life and seriously hinders economic development.At present,however,the effective and safe treatment to chronic pain remains a major medical problem.Hence,it is urgent and necessary to study and develop new types of analgesic technology.In recent years,ultrasound brain stimulation has received widespread attention as a new non-invasive neuromodulation technology,which was examined in the treatment of related diseases（Parkinson’s disease,epilepsy,etc.）and gained good progresses.Nevertheless,its feasibility to alleviate pain is still unclear.In addition,the effect of electrical-based deep brain stimulation as a traditional technique for pain suppression is still compromised due to the limited energy supply.Ultrasound-driven piezoelectric energy harvesting,as an emerging wireless energy transmission technology,has unique advantages in the field of biomedicine.Therefore,this paper proposed the research on development of ultrasonic transducers and brain stimulation for pain inhibition,which mainly includes three aspects:（1）By developing an ultrasonic transducer device（focused ultrasound generator）based on the inverse piezoelectric effect,non-invasive transcranial focused ultrasound brain stimulation and the analgesic research was conducted;（2）Through theoretical analysis,a new miniaturized,high-power wireless implantable ultrasonic transducer device（piezoelectric energy device）was designed and developed;（3）On the basis of the developed ultrasonic transducer device（piezoelectric energy device）based on the piezoelectric effect,the invasive deep brain electrical stimulation of ultrasound driven piezoelectric energy device and the analgesic effect was studied.Focused ultrasound transducer is a key component in transcranial focused ultrasound brain stimulation.Firstly,a self-focused ultrasound transducer with a center frequency of 650k Hz was designed and examined after the sound field simulation of transcranial ultrasound.Then,a formalin-induced pain animal model was applied to do electrophysiology analyses,and the results demonstrated that the transcranial focused ultrasound stimulation to the periaqueductal gray（PAG）brain area can significantly inhibit the enhancement of the local field potential（LFP）signal generated by formalin injection in the spinal cord L5 region.Furthermore,the experiments of the mechanism exploration,where the LFP signal of PAG brain area was collected simultaneously when this region was stimulated by transcranial focused ultrasound,indicated that ultrasound stimulation enhanced the brain activity of PAG brain area.Finally,the experiment of temperature measurement and the histological experiment of hematoxylin-eosin（HE）staining proved the safety of transcranial focused ultrasound stimulation.This study indicated that transcranial focused ultrasound brain stimulation can inhibit pain and provide a new method for non-invasive nerve stimulation analgesia technology.Piezoelectric energy devices made from traditional piezoelectric materials show very low energy density in vitro,and there are few reports on ultrasound-driven piezoelectric energy devices that can be effectively used for implantable brain stimulation for many years.In this paper,through theoretical analysis,material selection and structural design,a miniaturized,high-power wireless implantable piezoelectric energy device was developed.The device was based on a 6×6 array of high-performance Sm-doped Pb(Mg_1/3Nb_2/3)O₃-Pb Ti O₃（Sm-PMN-PT）piezoelectric single crystals,in which the piezoelectric coefficient(d₃₃),electromechanical coupling coefficient(k₃₃)and relative permittivity（ε）of Sm-PMN-PT were as high as 4000 p C/N,95%and 13000,respectively.The experimental results shown that the device had soft mechanical characteristic（up to 30°）and excellent electrical properties（instantaneous output power density was 1.1 W/cm²,which was 18 times the maximum reported at present）,providing a new idea for wireless energy transmission technology.In the study of brain stimulation of the ultrasound-driven piezoelectric energy device and analgesia,temperature and electrolysis tests were firstly conducted to verify that stimulation with a pulse repetition frequency of 50 Hz did not cause electrolysis or significant temperature changes.Additionally,electrophysiological experiments illustrated that ultrasound-driven piezoelectric energy device stimulation to the PAG brain area could significantly suppress the increase of spinal cord LFP signal induced by formalin.The neuronal activity of the PAG brain area could also be accurately regulated by adjusting the parameters of ultrasound.Next,the analgesic effect of the device in deep brain stimulation was determined by behavioral experiments in awake animals.Finally,the biocompatibility of this device in long-term implantation was proved by HE staining experiment and animal behavior observation.These results suggested that deep brain stimulation based on ultrasound-driven piezoelectric energy device can achieve deep brain stimulation and pain inhibition,providing a new way for deep brain stimulation analgesia technology.