Photons with a great many tunable physical properties have been profoundly engaged in research of brain science in all aspects for more than a hundred years. Taking advantage of highly developed incoherent light sources, coherent lasers and short-pulse lasers, innovative optical tools including both instrumentations and strategies have significantly boosted comprehensive research on neural science within a very short period. Right before China launches its Brain Project (Chinese version of BRAIN — Brain Research through Advancing Innovative Neurotechnologies) by the end of this year (2017), we are delighted to introduce to our readers a special issue on applications of bio-photonics in neuroscience and brain diseases.

Optical microscopy promises researchers to see most tiny substances directly. However, the resolution of conventional microscopy is restricted by the diffraction limit. This makes it a challenge to observe subcellular processes happened in nanoscale. The development of superresolution microscopy provides a solution to this challenge. Here, we briefly review several commonly used super-resolution techniques, explicating their basic principles and applications in biological science, especially in neuroscience. In addition, characteristics and limitations of each technique are compared to provide a guidance for biologists to choose the most suitable tool.

Rapid histology of brain tissues with su±cient diagnostic information has the great potential to aid neurosurgeons during operations. Stimulated Raman Scattering (SRS) microscopy is an emerging label-free imaging technique, with the intrinsic chemical resolutions to delineate brain tumors from normal tissues without the need of time-consuming tissue processing. Growing number of studies have shown SRS as a “virtual histology” tool for rapid diagnosis of various types of brain tumors. In this review, we focus on the basic principles and current developments of SRS microscopy, as well as its applications for brain tumor imaging.

Here, we discuss an important problem in medicine as development of effective strategies for brain drug delivery. This problem is related to the blood-brain barrier (BBB), which is a “customs” controlling the entrance of different molecules from blood into the brain protecting the normal function of central nervous system (CNS). We show three interfaces of anatomical side of BBB and two functional types of BBB — physical and transporter barriers. Although this protective mechanism is essential for health of CNS, it also creates a hindrance to the entry of drugs into the brain. The BBB was discovered over 100 years ago but till now, there is no effective methods for brain drug delivery. There are more than 70 approaches for overcoming BBB including physical, chemical and biological techniques but all of these tools have limitation to be widely used in clinical practice due to invasiveness, challenge in performing, very costly or limitation of drug concentration. Photodynamic therapy (PDT) is usual clinical method of surgical navigation for the resection of brain tumor and anti-cancer therapy. Nowadays, the application of PDT is considered as a potential promising tool for brain drug delivery via opening of BBB. Here, we show the first successful experimental results in this field discussing the adventures and disadvantages of PDT-related BBB disruption as well as alternatives to overcome these limitations and possible mechanisms with new pathways for brain clearance via glymphatic and lymphatic systems.

Despite intensive therapy regimen, brain cancers present with a poor prognosis, with an estimated median survival time of less than 15 months in case of glioblastoma. Early detection and improved surgical resections are suggested to enhance prognosis; several tools are being explored to achieve the purpose. Raman spectroscopy (RS), a nondestructive and noninvasive technique, has been extensively explored in brain cancers. This review summarizes RS-based studies in brain cancers, categorized into studies on animal models, ex vivo human samples, and in vivo human subjects. Findings suggest RS as a promising tool which can aid in improving the accuracy of brain tumor surgery. Further advancements in instrumentation, market-assessment, and clinical trials can facilitate translation of the technology as a noninvasive intraoperative guidance tool.

In vivo fiber photometry is a powerful technique to analyze the dynamics of population neurons during functional study of neuroscience. Here, we introduced a detailed protocol for fiber photometry-based calcium recording in freely moving mice, covering from virus injection, fiber stub insertion, optogenetical stimulation to data procurement and analysis. Furthermore, we applied this protocol to explore neuronal activity of mice lateral-posterior (LP) thalamic nucleus in response to optogenetical stimulation of primary visual cortex (V1) neurons, and explore axon clusters activity of optogenetically evoked V1 neurons. Final confirmation of virus-based protein expression in V1 and precise fiber insertion indicated that the surgery procedure of this protocol is reliable for functional calcium recording. The scripts for data analysis and some tips in our protocol are provided in details. Together, this protocol is simple, low-cost, and effective for neuronal activity detection by fiber photometry, which will help neuroscience researchers to carry out functional and behavioral study in vivo.

Light has been clinically utilized as a stimulation in medical treatment, such as Low-level laser therapy and photodynamic therapy, which has been more and more widely accepted in public. The penetration depth of the treatment light is important for precision treatment and safety control. The issue of light penetration has been highlighted in biomedical optics field for decades. However, quantitative research is sparse and even there are conflicts of view on the capability of near-infrared light penetration into brain tissue. This study attempts to quantitatively revisit this issue by innovative high-realistic 3D Monte Carlo modeling of stimulated light penetration within high-precision Visible Chinese human head. The properties of light, such as its wavelength, illumination profile and size are concern in this study. We made straightforward and quantitative comparisons among the effects by the light properties (i.e., wavelengths: 660, 810 and 980 nm; beam types: Gaussian and flat beam; beam diameters: 0, 2, 4 and 6 cm) which are in the range of light treatment. The findings include about 3% of light dosage within brain tissue; the combination of Gaussian beam and 810 nm light make the maximum light penetration (> 5 cm), which allows light to cross through gray matter into white mater. This study offered us, the first time as we know, quantitative guide for light stimulation parameter optimization in medical treatment.

Synchronized time-lens source is a novel method to generate synchronized optical pulses to modelocked lasers, and has found widespread applications in coherent Raman scattering microscopy. Relative timing jitter between the mode-locked laser and the synchronized time-lens source is a key parameter for evaluating the synchronization performance of such synchronized laser systems. However, the origins of the relative timing jitter in such systems are not fully determined, which in turn prevents the experimental efforts to optimize the synchronization performance. Here, we demonstrate, through theoretical modeling and numerical simulation, that the photodetection could be one physical origin of the relative timing jitter. Comparison with relative timing jitter due to the intrinsic timing jitter of the mode-locked laser is also demonstrated, revealing different qualitative and quantitative behaviors. Based on the nature of this photodetection-induced timing jitter, we further propose several strategies to reduce the relative timing jitter. Our theoretical results will provide guidelines for optimizing synchronization performance in experiments.

Background: Infrared laser stimulation has been proposed as an innovative method to elicit an auditory nerve response. Most studies have focused on using long-wavelength infrared (> 980 nm) pulsed lasers with high water absorption coe±cients. This paper sought to assess whether a shortwavelength laser (465 nm) with an absorption coe±cient as low as 10-3 cm-1 would activate the auditory nerve and studied its potential mechanism. Method: Optical compound action potentials (OCAPs) were recorded when synchronous trigger laser pulses stimulate the cochlea before and after deafening, varying the pulse durations (from 800 μs to 3600 μs) and the amount of radiant energy (from 18.05 mJ/cm2 to 107.91 mJ/cm2). A thermal infrared imager was applied to monitor the temperature change of the guinea pig cochlea. Results: The results showed that pulsed laser stimulation at 465nm could invoke OCAPs and had a similar waveform compared to the acoustical compound action potentials. The amplitude of OCAPs had a positive correlation with the increasing laser peak power, while the latency of OCAPs showed a negative correlation. The imager data showed that the temperature in the cochlea rose quickly by about 0.3C right after stimulating the cochlea and decreased quickly back to the initial temperature as the stimulation ended. Conclusions: This paper demonstrates that 465-nm laser stimulation can successfully induce OCAPs outside the cochlea, and that the amplitude and latency of the invoked OCAPs are highly affected by laser peak power. This paper proposes that a photothermal effect might be the main mechanism for the auditory nerve response induced by short-wavelength laser stimulation.

Based on the laser speckle contrast imaging (LSCI) and the multiscale entropy (MSE), we study in this work the blood flow dynamics at the levels of cerebral veins and the surrounding network of microcerebral vessels. We discuss how the phenylephrine-related acute peripheral hypertension is reflected in the cerebral circulation and show that the observed changes are scale-dependent, and they are significantly more pronounced in microcerebral vessels, while the macrocerebral dynamics does not demonstrate authentic inter-group distinctions. We also consider the permeability of blood-brain barrier (BBB) and study its opening caused by sound exposure. We show that alterations associated with the BBB opening can be revealed by the analysis of blood flow at the level of macrocerebral vessels.

We present a three-dimensional (3D) isotropic imaging of mouse brain using light-sheet fluorescent microscopy (LSFM) in conjunction with a multi-view imaging computation. Unlike common single view LSFM is used for mouse brain imaging, the brain tissue is 3D imaged under eight views in our study, by a home-built selective plane illumination microscopy (SPIM). An output image containing complete structural information as well as significantly improved resolution (～4 times) are then computed based on these eight views of data, using a bead-guided multi-view registration and deconvolution. With superior imaging quality, the astrocyte and pyramidal neurons together with their subcellular nerve fibers can be clearly visualized and segmented. With further including other computational methods, this study can be potentially scaled up to map the connectome of whole mouse brain with a simple light-sheet microscope.

Interpreting the biochemical specificity of spinal cord tissue is the essential requirement for understanding the biochemical mechanisms during spinal-cord-related pathological course. In this work, a longitudinal study was implemented to reveal a precise linkage between the spectral features and the molecular composition in ex vivo mouse spinal cord tissue by microspectral Raman imaging. It was testified that lipid-rich white matter could be distinguished from gray matter not only by the lipid Raman peaks at 1064, 1300, 1445 and 1660 cm-1, but also by protein (1250 and 1328 cm-1) and saccharides (913 and 1137 cm-1) distributions. K-means cluster analysis was further applied to visualize the morphological basis of spinal cord tissue by chemical components and their distribution patterns. Two-dimensional chemical images were then generated to visualize the contrast between two different tissue types by integrating the intensities of the featured Raman bands. All the obtained results illustrated the biochemical characteristics of spinal cord tissue, as well as some specific substance variances between different tissue types, which formed a solid basis for the molecular investigation of spinal cord pathological alterations.