## 4 PAI in Combination with Other Imaging Techniques
Experimental results showed that real-time noninvasive PAI, in combination with other neuroimaging modalities, successfully produced a rapid TBI diagnosis, the rapid monitoring of TBI dynamics and long-term longitudinal preclinical monitoring of precision-targeted TBI therapies. Dual-mode US and PAI imaging is increasingly used in preclinical applications because they provide both anatomical and functional information. Combined with PAI with contrast enhancement agents and delivered to the brain by FUS BBB opening, the capabilities of dual-mode imaging can be extended to the real-time visualization of molecular properties and drug delivery in the brain at a depth of several centimeters without craniotomy. [PERSON] et al. developed a multiple-mode US-guided PAI technique using the commercial Vevo LAZR PA apparatus (VisualSonics, Inc., Toronto, ON, Canada) [82]. Their system delivered silica-coated gold nanorods with strong NIR absorption characteristics to the brain, via a microbubble-assisted FUS BBB opening. These nanorods functioned as an imaging contrast enhancement agent for longitudinal diagnostic imaging and for the therapeutic monitoring of neurological diseases. Therefore, the method has the potential to act as a highly useful tool for understanding the mechanisms of neurological disorders and for evaluating appropriate treatment choices. Devising a method for non-invasive PA brain imaging, which is different from PA body tissue imaging, has proved challenging, largely due to the skull bone, which has a considerable effect on acoustic attenuation, aberration and reverberation. There exists a considerable disparity between acoustic impedance in the skull bone and in soft brain tissue. As a result, before propagating outside the skull, PA waves experience great attenuation, acoustic mode conversion between longitudinal and shear waves and wave reverberations at the two skull boundaries. These disadvantages complicate accurate image reconstruction. [PERSON]'s group systematically investigated the impact of murine skull on PA wave propagation and the corresponding PAI image reconstruction [83]. Their results confirmed that transcranial PACT displayed an inferior image quality compared with transcranial PAM (seen Figure 5), even in instances where the two modalities use a similar US frequency and effective detection aperture. Moreover, they established that phase aberration, which is caused by different longitudinal wave speeds in the skull and the surrounding soft tissues is a major reason for the transcranial PACT's image artifacts. One potential solution is to develop an adaptive image reconstruction method that can incorporate inhomogeneous wave speeds to numerically reduce the phase aberration. This method typically benefits from acquiring prior information regarding the skull's geometry and acoustic properties, which can be determined using the US technique. Phase aberration can also be reduced by chemically softening the skull to reduce longitudinal wave speeds. Another major contributor to image artifacts is mode conversion at skull boundaries. However, [PERSON]'s group found that direct transmission of shear wave-converted longitudinal waves was less affected by distortions introduced by the skull and resulted in an improved reconstructed image quality with less artifacts. Wave reverberations, on the other hand, primarily caused image artifacts in deeper brain regions, where the useful signals (or directly transmitted signals) are often weak too. Reverberation artifacts may be reduced by applying low-pass filtering before the image reconstruction, because reverberation waves follow a longer acoustic path length within the skull and possess more high-frequency components than directly transmitted waves. Other methods include the application of a first-of-a-kind dictionary learning algorithm [43], or the removal of late-arrived signals in half-time image reconstruction [84].