Manipulation of brain circuits is a critical to understanding how brain controls behaviors under normal physiological conditions and how its dysfunction causes diseases. Ultrasound stimulation is an emerging neuromodulation modality that allows activation of neurons with acoustic waves. However, the piezo based transcranial ultrasound stimulation offers poor spatial resolution, which hinders the understanding of its mechanism as well as application in region specific activation in small animals. To address this limitation, we developed a series of neuromodulation techniques utilizing the photon to sound conversion capability offered by the optoacoustic effect. In chapter 2, we developed a fiber based optoacoustic converter th-at allows neural stimulation at submillimeter spatial precision both in vitro and in vivo. In chapter 3, the spatial resolution was further improved by tapered fiber optoacoustic emitter to achieve stimulation of single neurons and even subcellular structures in culture. In chapter 4, we developed photoacoustic nanoparticle based neural stimulation that allows direct activation of neurons through optoacoustic waves generated by nanoparticles bonded to the neuronal membrane. Finally, in chapter 5, in an effort to improve penetration depth, a split ring resonator based microwave neuromodulation was developed that allows wireless stimulation and inhibition of neurons with subwavelength spatial resolution. Together, these methods offer an enabling platform with opportunities to understand the mechanism of acoustic neural stimulation as well as potential for treatment of neurological diseases with high precision neuromodulation.

Cell modulation poses an invaluable role in understanding the biophysics, deciphering the neural circuits, and exploring clinical treatment of diseases. Optoacoustic cell modulation is an emerging modality benefiting from the merits of ultrasound with high penetration depth as well as photons with high spatial precision. My thesis work focused on the development of a fiber optoacoustic emitter for neural stimulation and the study of biomolecular mechanisms underlying optoacoustic cell modulation. To enable region specific and high-efficiency cell modulation, we developed a fiber-based optoacoustic emitter (FOE), serving as a miniaturized ultrasound point source, with sub-millimeter confinement. By modifying acoustic damping and light absorption performance, controllable frequencies in the range of 0.083 MHz to 5.500 MHz are achieved and further induce cell membrane sonoporation with frequency dependent efficiency. These data demonstrate the potential of FOE in region-specific drug delivery, gene transfection and neurostimulation. To achieve neuromodulation at single cell spatial resolution, we further developed a tapered fiber optoacoustic emitter (TFOE) enabling stimulation of single neurons and subcellular structures. The highly confined ultrasound enabled integration of the optoacoustic stimulation with stable patch clamp recording on single neurons for the first time. Cell-type-specific response of excitatory and inhibitory neurons to acoustic stimulation was unveiled. Towards understanding the biomolecular mechanisms of optoacoustic cell modulation, we show that optoacoustic excites primary cortical neurons through specific calcium-selective mechanosensitive ion channels with the assistant of calcium amplifier channel and voltage-gated channels. Pharmacological inhibition of specific ion channels leads to reduced responses, while over-expressing these channels results in stronger stimulation. These results shed new insights into the mechanism of ultrasound neurostimulation. Together, these findings offer a platform for understanding the mechanism of acoustic cell modulation as well as non-genetic, high precision cell modulation method enabling treatment of diseases. / 2025-09-21T00:00:00Z

Photoacoustic computed tomography (PAT) has great potential for application in the biomedical field. It best combines the high contrast of electromagnetic absorption and the high resolution of ultrasonic waves in biological tissues. In Chapter II, we present time-domain reconstruction algorithms for PAT. First, a formal reconstruction formula for arbitrary measurement geometry is presented. Then, we derive a universal and exact back-projection formula for three commonly used measurement geometries, including spherical, planar and cylindrical surfaces. We also find this back-projection formula can be extended to arbitrary measurement surfaces under certain conditions. A method to implement the back-projection algorithm is also given. Finally, numerical simulations are performed to demonstrate the performance of the back-projection formula. In Chapter III, we present a theoretical analysis of the spatial resolution of PAT for the first time. The three common geometries as well as other general cases are investigated. The point-spread functions (PSF's) related to the bandwidth and the sensing aperture of the detector are derived. Both the full-width-at-half-maximum of the PSF and the Rayleigh criterion are used to define the spatial resolution. In Chapter IV, we first present a theoretical analysis of spatial sampling in the PA measurement for three common geometries. Then, based on the sampling theorem, we propose an optimal sampling strategy for the PA measurement. Optimal spatial sampling periods for different geometries are derived. The aliasing effects on the PAT images are also discussed. Finally, we conduct numerical simulations to test the proposed optimal sampling strategy and also to demonstrate how the aliasing related to spatially discrete sampling affects the PAT image. In Chapter V, we first describe a prototype of the RF-induced PAT imaging system that we have built. Then, we present experiments of phantom samples as well as a preliminary study of breast imaging for cancer detection.

The application of photoacoustic (PA) phenomena to medical imaging has been investigated for more than a decade. To implement this modality, one may choose between two types of laser sources, pulsed or continuous wave (CW). This selection affects all features of the imaging technique. Nowadays pulsed lasers are the state-of-the-art technique in the PA research. In this work, various features of the alternative frequency-domain (FD) PA were investigated. An axially symmetric transfer function model of PA wave generation and a Krimholtz-Leedom-Matthaei (KLM) transducer model were developed and used to analyze the experimental results. The controllable parameters of the FD-PA were optimized to improve the signal-to-noise ratio (SNR), contrast, axial resolution and depth detectivity. For example, it was shown that employing the optimal chirp bandwidth can enhance the SNR by more than 10 dB. In addition to the image produced by the cross-correlation amplitude, the phase of the correlation signal was used as a separate channel. A statistical method was introduced to generate an image from this phase channel, and also to filter the PA amplitude channel. A study was also performed to compare FD PA and the prevalent pulsed method. Various features of both methods were examined experimentally using a dual-mode PA system and under the condition of maximum permissible exposure (MPE). The SNRs of both methods were evaluated theoretically and experimentally. It was shown that at low frequencies, both modalities generate comparable SNRs, and at high frequencies pulsed PA produces superior SNRs and depth detetivity. However, by increasing the laser power and decreasing the chirp duration within the safety limits, the SNR and depth detectivity of the FD-PA method are enhanced considerably. The main cause to achieve lower experimental SNRs than theoretical predictions for pulsed PA response was shown to be the oscillating baseline, which can be partially eliminated by filtering.

The application of photoacoustic (PA) phenomena to medical imaging has been investigated for more than a decade. To implement this modality, one may choose between two types of laser sources, pulsed or continuous wave (CW). This selection affects all features of the imaging technique. Nowadays pulsed lasers are the state-of-the-art technique in the PA research. In this work, various features of the alternative frequency-domain (FD) PA were investigated. An axially symmetric transfer function model of PA wave generation and a Krimholtz-Leedom-Matthaei (KLM) transducer model were developed and used to analyze the experimental results. The controllable parameters of the FD-PA were optimized to improve the signal-to-noise ratio (SNR), contrast, axial resolution and depth detectivity. For example, it was shown that employing the optimal chirp bandwidth can enhance the SNR by more than 10 dB. In addition to the image produced by the cross-correlation amplitude, the phase of the correlation signal was used as a separate channel. A statistical method was introduced to generate an image from this phase channel, and also to filter the PA amplitude channel. A study was also performed to compare FD PA and the prevalent pulsed method. Various features of both methods were examined experimentally using a dual-mode PA system and under the condition of maximum permissible exposure (MPE). The SNRs of both methods were evaluated theoretically and experimentally. It was shown that at low frequencies, both modalities generate comparable SNRs, and at high frequencies pulsed PA produces superior SNRs and depth detetivity. However, by increasing the laser power and decreasing the chirp duration within the safety limits, the SNR and depth detectivity of the FD-PA method are enhanced considerably. The main cause to achieve lower experimental SNRs than theoretical predictions for pulsed PA response was shown to be the oscillating baseline, which can be partially eliminated by filtering.

Dans ce travail de thèse, nous étudions expérimentalement la dynamique vibrationnelle de nano-objets uniques métalliques ou semi-conducteurs par des techniques pompe/sonde femtosecondes. Nous démontrons d’abord que l’observation de nanofils uniques, suspendus au-dessus de tranchées permet à la fois de s’affranchir de l’effet d’étalement inhomogène des propriétés acoustiques et d’augmenter le confinement acoustique. Grâce à l’enrichissement du paysage vibrationnel ainsi obtenu, nous explorons les propriétés élastiques de nombreux systèmes : métalliques, semi-conducteurs, poreux, alliages, cœur/coquille, etc. Ensuite, nous tirons parti de l’augmentation du confinement acoustique pour observer la propagation d’ondes acoustiques gigahertz guidées le long de nanofils ou de nanopoutres. Nous montrons que la propagation de ces ondes acoustiques dans ces guides d’ondes nanométriques permet d’obtenir des informations indépendantes sur les propriétés élastiques des objets. A contrario, nous mettons en évidence que lorsque le nanofil est en contact avec un substrat, il agit comme une source acoustique monochromatique d’ondes longitudinales qui rayonne dans le substrat. Nous réalisons en transmission l’imagerie spatio-temporelle de ce champ acoustique généré et détectons acoustiquement l’orientation du nanofil sous-jacent grâce à l’anisotropie de forme du champ acoustique. Enfin, nous envisageons une preuve de concept d’un système de microscopie acoustique de résolution spatiale nanométrique en utilisant une pointe de microscopie à force atomique. / Vibrational dynamics of individual nano-objects is studied experimentally using pump and probe time-resolved spectroscopy. First, suspended and individual nano-objects avoid the inhomogeneous broadening of the acoustic properties and increase the acoustics confinement inside the nano-object. Elastic properties of metallic, semiconducting, porous, alloys or core-shell nanowires are thus studied in this advantageous geometry. The increased acoustic confinement in the suspended geometry also lead us to the observation of gigahertz coherent guided acoustic phonons in single copper nanowires and gold nanobeams. We show that the observation of propagating acoustic waves in nanoscale waveguides provide additional elastic informations. Furthermore, it gives the opportunity to unambiguously discriminate which mode is excited and detected using pump and probe time-resolved spectroscopy. On the contrary, nanowires can be used as monochromatic acoustic sources of longitudinal waves when deposited on a substrate. As the acoustic source radiates longitudinal waves inside the substrate, the spatiotemporal imaging of the generated acoustic field is undergone and the nanowire’s orientation is detected in transmission thanks to the acoustic field’s anisotropy. Finally, as another step toward acoustic microscopy with nanoscale spatial resolutions, an atomic force microscopy tip is used as a waveguide and an acoustic transducer with nanometric spatial extension.