Deep Brain Tissue Research Articles

Deep Learning-Based Multiclass Brain Tissue Segmentation in Fetal MRIs

Fetal brain tissue segmentation is essential for quantifying the presence of congenital disorders in the developing fetus. Manual segmentation of fetal brain tissue is cumbersome and time-consuming, so using an automatic segmentation method can greatly simplify the process. In addition, the fetal brain undergoes a variety of changes throughout pregnancy, such as increased brain volume, neuronal migration, and synaptogenesis. In this case, the contrast between tissues, especially between gray matter and white matter, constantly changes throughout pregnancy, increasing the complexity and difficulty of our segmentation. To reduce the burden of manual refinement of segmentation, we proposed a new deep learning-based segmentation method. Our approach utilized a novel attentional structural block, the contextual transformer block (CoT-Block), which was applied in the backbone network model of the encoder-decoder to guide the learning of dynamic attentional matrices and enhance image feature extraction. Additionally, in the last layer of the decoder, we introduced a hybrid dilated convolution module, which can expand the receptive field and retain detailed spatial information, effectively extracting the global contextual information in fetal brain MRI. We quantitatively evaluated our method according to several performance measures: dice, precision, sensitivity, and specificity. In 80 fetal brain MRI scans with gestational ages ranging from 20 to 35 weeks, we obtained an average Dice similarity coefficient (DSC) of 83.79%, an average Volume Similarity (VS) of 84.84%, and an average Hausdorff95 Distance (HD95) of 35.66 mm. We also used several advanced deep learning segmentation models for comparison under equivalent conditions, and the results showed that our method was superior to other methods and exhibited an excellent segmentation performance.

Transcranial deep-tissue phototherapy for Alzheimer's disease using low-dose X-ray-activated long-afterglow scintillators

Non-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-β (Aβ) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aβ oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Here, we report an Aβ targeted, low-dose X-ray-excitable long-afterglow scintillator (ScNPs@RB/Ab) for efficient deep-brain phototherapy. We demonstrate that the as-synthesized ScNPs@RB/Ab is capable of converting X-rays into visible light to activate the photosensitizers of rose bengal (RB) for Aβ oxygenation through the scalp and skull. We show that the ScNPs@RB/Ab persistently emitting visible luminescence can substantially minimize the risk of excessive X-ray exposure dosage. Importantly, peptide KLVFFAED-functionalized ScNPs@RB/Ab shows a blood–brain barrier permeability. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aβ burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects. Our study paves a new pathway to develop high-efficiency transcranial AD phototherapy. Statement of significanceNon-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-β (Aβ) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aβ oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Herein, we report an Aβ targeted, low-dose X-ray-excitable long-afterglow scintillators (ScNPs@RB/Ab) for efficient deep-brain phototherapy. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aβ burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects.

Single-Step Fast Tissue Clearing of Thick Mouse Brain Tissue for Multi-Dimensional High-Resolution Imaging.

Recent advances in optical clearing techniques have dramatically improved deep tissue imaging by reducing the obscuring effects of light scattering and absorption. However, these optical clearing methods require specialized equipment or a lengthy undertaking with complex protocols that can lead to sample volume changes and distortion. In addition, the imaging of cleared tissues has limitations, such as fluorescence bleaching, harmful and foul-smelling solutions, and the difficulty of handling samples in high-viscosity refractive index (RI) matching solutions. To address the various limitations of thick tissue imaging, we developed an Aqueous high refractive Index matching and tissue Clearing solution for Imaging (termed AICI) with a one-step tissue clearing protocol that was easily made at a reasonable price in our own laboratory without any equipment. AICI can rapidly clear a 1 mm thick brain slice within 90 min with simultaneous RI matching, low viscosity, and a high refractive index (RI = 1.466), allowing the imaging of the sample without additional processing. We compared AICI with commercially available RI matching solutions, including optical clear agents (OCAs), for tissue clearing. The viscosity of AICI is closer to that of water compared with other RI matching solutions, and there was a less than 2.3% expansion in the tissue linear morphology during 24 h exposure to AICI. Moreover, AICI remained fluid over 30 days of air exposure, and the EGFP fluorescence signal was only reduced to ~65% after 10 days. AICI showed a limited clearing of brain tissue >3 mm thick. However, fine neuronal structures, such as dendritic spines and axonal boutons, could still be imaged in thick brain slices treated with AICI. Therefore, AICI is useful not only for the three-dimensional (3D) high-resolution identification of neuronal structures, but also for the examination of multiple structural imaging by neuronal distribution, projection, and gene expression in deep brain tissue. AICI is applicable beyond the imaging of fluorescent antibodies and dyes, and can clear a variety of tissue types, making it broadly useful to researchers for optical imaging applications.

Nanoscale‐tipped wire array injections transfer DNA directly into brain cells ex vivo and in vivo

Genetic modification to restore cell functions in the brain can be performed through the delivery of biomolecules in a minimally invasive manner into live neuronal cells within brain tissues. However, conventional nanoscale needles are too short (lengths of ~10 µm) to target neuronal cells in ~1‐mm‐thick brain tissues because the neuronal cells are located deep within the tissue. Here, we report the use of nanoscale‐tipped wire (NTW) arrays with diameters < 100 nm and wire lengths of ~200 µm to address biomolecule delivery issues. The NTW arrays were manufactured by growth of silicon microwire arrays and nanotip formation. This technique uses pinpoint, multiple‐cell DNA injections in deep areas of brain tissues, enabling target cells to be marked by fluorescent protein (FP) expression vectors. This technique has potential for use for electrophysiological recordings and biological transfection into neuronal cells. Herein, simply pressing an NTW array delivers and expresses plasmid DNA in multiple‐cultured cells and multiple‐neuronal cells within a brain slice with reduced cell damage. Additionally, DNA transfection is demonstrated using brain cells ex vivo and in vivo. Moreover, knockdown of a critical clock gene after injecting a short hairpin RNA (shRNA) and a genome‐editing vector demonstrates the potential to genetically alter the function of living brain cells, for example, pacemaker cells of the mammalian circadian rhythms. Overall, our NTW array injection technique enables genetic and functional modification of living cells in deep brain tissue areas, both ex vivo and in vivo.

Development of a Monte Carlo-wave model to simulate time domain diffuse correlation spectroscopy measurements from first principles.

.Significance: Diffuse correlation spectroscopy (DCS) is an optical technique that measures blood flow non-invasively and continuously. The time-domain (TD) variant of DCS, namely, TD-DCS has demonstrated a potential to improve brain depth sensitivity and to distinguish superficial from deeper blood flow by utilizing pulsed laser sources and a gating strategy to select photons with different pathlengths within the scattering tissue using a single source–detector separation. A quantitative tool to predict the performance of TD-DCS that can be compared with traditional continuous wave DCS (CW-DCS) currently does not exist but is crucial to provide guidance for the continued development and application of these DCS systems.Aims: We aim to establish a model to simulate TD-DCS measurements from first principles, which enables analysis of the impact of measurement noise that can be utilized to quantify the performance for any particular TD-DCS system and measurement geometry.Approach: We have integrated the Monte Carlo simulation describing photon scattering in biological tissue with the wave model that calculates the speckle intensity fluctuations due to tissue dynamics to simulate TD-DCS measurements from first principles.Results: Our model is capable of simulating photon counts received at the detector as a function of time for both CW-DCS and TD-DCS measurements. The effects of the laser coherence, instrument response function, detector gate delay, gate width, intrinsic noise arising from speckle statistics, and shot noise are incorporated in the model. We have demonstrated the ability of our model to simulate TD-DCS measurements under different conditions, and the use of our model to compare the performance of TD-DCS and CW-DCS under a few typical measurement conditions.Conclusion: We have established a Monte Carlo-Wave model that is capable of simulating CW-DCS and TD-DCS measurements from first principles. In our exploration of the parameter space, we could not find realistic measurement conditions under which TD-DCS outperformed CW-DCS. However, the parameter space for the optimization of the contrast to noise ratio of TD-DCS is large and complex, so our results do not imply that TD-DCS cannot indeed outperform CW-DCS under different conditions. We made our code available publicly for others in the field to find use cases favorable to TD-DCS. TD-DCS also provides a promising way to measure deep brain tissue dynamics using a short source–detector separation, which will benefit the development of technologies including high density DCS systems and image reconstruction using a limited number of source–detector pairs.

Risk factors of cerebral microbleeds in young and middle-aged patients with hypertension

Background &amp; Objectives: This study aimed to explore the incidence and potential risk factors of cerebral microbleeds (CMBs) in young and middle-aged patients with hypertension. Methods: We retrospectively analyzed the clinical data of young and middle-aged patients with hypertension in the Department of Neurology, General Hospital of Western Theater Command, Chengdu, China between August 2018 and December 2020. The demographic baseline, laboratory parameters and clinical imaging data were collected. Microbleed anatomical rating scale (MARS) was applied to evaluate the presence, amount, and topographical distributions of CMBs. Results: Among 196 young and middle-aged patients with hypertension, 84 (42.9%) patients had CMBs. CMBs were more likely to occur in the deep brain tissue regions (41.8%), followed by lobar or infratentorial region. White matter hyperintensity (OR, 5.262; 95%CI, 1.314-21.075; P=0.019), abnormal lipid metabolism (OR, 3.832; 95%CI, 1.578-9.306; P=0.003), usage of anti-platelet aggregation drugs (OR, 2.947; 95%CI, 1.138-7.632; P=0.026), smoking history (OR, 3.218; 95%CI, 1.073-9.651; P=0.037), and hyperhomocysteinemia (OR, 1.415; 95%CI, 1.018-1.967; P=0.039) were independently associated with deep or infratentorial CMBs in young and middle-aged patients with hypertension. However, the occurrence of strictly lobar CMBs was only independently associated with abnormal lipid metabolism (OR, 4.162; 95%CI, 1.685-10.282; P=0.002). Conclusions: The rate of CMBs was high in young and middle-aged patients with hypertension, most commonly occurring in the deep brain tissue region. While multiple risk factors were identified to be associated with deep or infratentorial CMBs, the occurrence of strictly lobar CMBs was only associated with abnormal lipid metabolism.

Automated workflow for volumetric assessment of signal intensity ratio on T1-weighted MR images after multiple gadolinium administrations

Purpose: Repeated injections of linear gadolinium-based contrast agent (GBCA) have shown correlations with increased signal intensities (SI) on unenhanced T1-weighted (T1w) images. Assessment is usually performed manually on a single slice and the SI as an average of a freehand region-of-interest is reported. We aim to develop a fully automated software that segments and computes SI ratio of dentate nucleus (DN) to pons (DN/P) and globus pallidus (GP) to thalamus (GP/T) for the assessment of gadolinium presence in the brain after a serial GBCA administrations. Approach: All patients ( ) underwent at least eight GBCA enhanced scans. The modal SI in the DN, GP, pons, and thalamus were measured volumetrically on unenhanced T1w images and corrected based on the reference protocol (measurement 1) and compared to the SI-uncorrected-modal-volume (measurement 2), SI-corrected-mean-volume (measurement 3), as well as SI-corrected-modal-single slice (measurement 4) approaches. Results: Automatic processing worked on all 2119 studies (1150 at 1.5T and 969 at 3T). DN/P were (1.5T) and (3T). GP/T were (1.5T) and (3T). Modal DN/P ratios from volumetric assessment at 1.5T failed to show a statistical difference with or without SI corrections ( ). All other -tests demonstrated significant differences (measurement 2, 3, 4 compared to 1, ). Conclusion: The fully automatic method is an effective powerful tool to streamline the analysis of SI ratios in the deep brain tissues. Divergent SI ratios using different approaches reinforces the need to standardize the measurement for the research in this field.

Optical Coherence Tomography Angiography: A Window into Central Nervous System Neurodegeneration

Optical coherence tomography angiography (OCT-A) allows noninvasive visualization of intraocular tissues with high resolution. Recently, an innovative use of this technology in studying neurodegenerative diseases has emerged with the neurosensory retina as a unique window into deeper brain tissues. Here, we discuss its role in identifying biomarkers of neurodegenerative diseases.

Bio-Heat Model of Kilohertz-Frequency Deep Brain Stimulation Increases Brain Tissue Temperature

Early clinical trials suggest that deep brain stimulation at kilohertz frequencies (10 kHz-DBS) may be effective in improving motor symptoms in patients with movement disorders. The 10 kHz-DBS can deliver significantly more power in tissue compared to conventional frequency DBS, reflecting increased pulse compression (duty cycle). We hypothesize that 10 kHz-DBS modulates neuronal function through moderate local tissue heating, analogous to kilohertz spinal cord stimulation (10 kHz-SCS). To establish the role of tissue heating in 10 kHz-DBS (30 μs, 10 kHz, at intensities of 3-7 mApeak ), a decisive first step is to characterize the range of temperature changes during clinical kHz-DBS protocols. We developed a high-resolution magnetic resonance imaging-derived DBS model incorporating joule-heat coupled bio-heat multi-physics to establish the role of tissue heating. Volume of tissue activated (VTA) under assumptions of activating function (for 130 Hz) or heating (for 10 kHz) based neuromodulation are contrasted. DBS waveform power (waveform RMS) determined joule heating at the deep brain tissues. Peak heating was supralinearly dependent on stimulation RMS. The 10 kHz-DBS stimulation with 2.3 to 5.4 mARMS (corresponding to 3 to 7 mApeak ) produced 0.10 to 1.38°C heating at the subthalamic nucleus (STN) target under standard tissue parameters. Maximum temperature increases were predicted inside the electrode encapsulation layer (enCAP) with 2.3 to 5.4 mARMS producing 0.13 to 1.87°C under standard tissue parameters. Tissue parameter analysis predicted STN heating was especially sensitive (ranging from 0.44 to 1.35°C at 3.8 mARMS ) to decreasing enCAP electrical conductivity and decreasing STN thermal conductivity. Subject to validation with in vivo measurements, neuromodulation through a heating mechanism of action by 10 kHz-DBS can indicate novel therapeutic pathways and strategies for dose optimization.

Infrared neural stimulation and inhibition using an implantable silicon photonic microdevice

Brain is one of the most temperature sensitive organs. Besides the fundamental role of temperature in cellular metabolism, thermal response of neuronal populations is also significant during the evolution of various neurodegenerative diseases. For such critical environmental factor, thorough mapping of cellular response to variations in temperature is desired in the living brain. So far, limited efforts have been made to create complex devices that are able to modulate temperature, and concurrently record multiple features of the stimulated region. In our work, the in vivo application of a multimodal photonic neural probe is demonstrated. Optical, thermal, and electrophysiological functions are monolithically integrated in a single device. The system facilitates spatial and temporal control of temperature distribution at high precision in the deep brain tissue through an embedded infrared waveguide, while it provides recording of the artefact-free electrical response of individual cells at multiple locations along the probe shaft. Spatial distribution of the optically induced temperature changes is evaluated through in vitro measurements and a validated multi-physical model. The operation of the multimodal microdevice is demonstrated in the rat neocortex and in the hippocampus to increase or suppress firing rate of stimulated neurons in a reversible manner using continuous wave infrared light (λ = 1550 nm). Our approach is envisioned to be a promising candidate as an advanced experimental toolset to reveal thermally evoked responses in the deep neural tissue.

Preclinical Model of Optical Coherence Tomography for High-Resolution Deep-Brain Imaging for Laser Ablation.

HomeRadiology: Imaging CancerVol. 2, No. 3 PreviousNext Research HighlightsFree AccessPreclinical Model of Optical Coherence Tomography for High-Resolution Deep-Brain Imaging for Laser AblationAdeline N. BoettcherAdeline N. BoettcherAdeline N. BoettcherPublished Online:May 29 2020https://doi.org/10.1148/rycan.2020204016MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked InEmail Take-Away Points■ Major Focus: Preclinical in vivo imaging of the deep brain using an optical coherence tomography (OCT) needle for tissue visualization and laser ablation.■ Key Result: OCT imaging in a murine model was capable of producing high-resolution images of the deep brain before and after laser ablation at a resolution of 1.7 μm (axial) × 5.7 μm (lateral).■ Impact: Development of this tool for deep-brain imaging and ablation would allow for more precise and real-time imaging during ablation procedures in clinical practice.High-resolution three-dimensional imaging would be beneficial for viewing solid organs for planning and monitoring of cancer ablation therapies. Typical laser ablation procedures require MRI to determine where the target lesion is located, to confirm placement of the ablation probe, and to observe the effect of ablation during the procedure. For sensitive imaging areas, such as the brain, time needed for MRI to verify probe positioning and possible repositioning increases risk of injury to the patient. Together, a real-time high-resolution imaging technique that could overcome these issues would be beneficial for planning and monitoring of solid organ ablation procedures.In this study, Yuan et al assembled an 800-nm optical coherence tomography (OCT) imaging needle that was capable of high-resolution imaging (1.7 μm [axial] × 5.7 μm [lateral]). Additionally, this needle was equipped with a near-infrared laser for tissue ablation. For their first proof-of-concept study, the group imaged brain tissue in mice by introducing the microneedle through two burr holes made in the skull. Three-dimensional, color-coded images were generated by imaging a 4.5-mm-long cylindrical volume in the deep brain. Images detected even filament bundles in deep brain tissues. The authors also successfully imaged brain tumors marked with green fluorescent protein. Images from both normal and malignant brain tissue showed high concordance to histology.To demonstrate potential imaging laser ablation procedures in patients, the authors imaged mouse brains before and immediately after laser ablation. By assessing volumetric OCT brain images, the authors verified successful laser ablation of the target volume demonstrated by histology. Taken together, the authors show exciting first steps toward developing an OCT microneedle for real-time high-resolution clinical imaging and precision laser ablation of solid organ tumors, such as glioblastomas.Highlighted ArticleYuan W, Chen D, Sarabia-Estrada R, et al. Theranostic OCT microneedle for fast ultrahigh-resolution deep-brain imaging and efficient laser ablation in vivo. Sci Adv 2020;6(15):eaaz9664. doi: 10.1126/sciadv.aaz9664Highlighted ArticleYuan W, Chen D, Sarabia-Estrada R, et al. Theranostic OCT microneedle for fast ultrahigh-resolution deep-brain imaging and efficient laser ablation in vivo. Sci Adv 2020;6(15):eaaz9664. doi: 10.1126/sciadv.aaz9664 Crossref, Medline, Google ScholarArticle HistoryPublished online: May 29 2020 FiguresReferencesRelatedDetailsRecommended Articles Image-guided Microinvasive Percutaneous Treatment of Breast Lesions: Where Do We Stand?RadioGraphics2021Volume: 41Issue: 4pp. 945-966Effects of a Thermal Accelerant Gel on Microwave Ablation Zone Volumes in Lung: A Porcine StudyRadiology2019Volume: 291Issue: 2pp. 504-510Development of Multispectral Optoacoustic Tomography as a Clinically Translatable Modality for Cancer ImagingRadiology: Imaging Cancer2020Volume: 2Issue: 6High-Intensity Focused Ultrasound for Pain Management in Patients with CancerRadioGraphics2018Volume: 38Issue: 2pp. 603-623Focused Ultrasound Hyperthermia for Targeted Drug Release from Thermosensitive Liposomes: Results from a Phase I TrialRadiology2019Volume: 291Issue: 1pp. 232-238See More RSNA Education Exhibits Diagnostic and Procedural Intraoperative Ultrasound: Technique, Tips, and Tricks for Optimizing ResultsDigital Posters2019Novel Image-Guided Micro-Invasive Percutaneous Treatments of Breast Lesions: Where Do We Stand?Digital Posters2019Five Stages of Artifacts: Denial, Anger, Bargaining, Depression, and AcceptanceDigital Posters2019 RSNA Case Collection Cerebral Air EmboliRSNA Case Collection2021Medial Temporal Lobe EncephaloceleRSNA Case Collection2021Trigeminal schwannomaRSNA Case Collection2020 Vol. 2, No. 3 Metrics Downloaded 156 times Altmetric Score PDF download

Modular Current Stimulation System for Pre-clinical Studies.

Electric stimulators with precise and reliable outputs are an indispensable part of electrophysiological research. From single cells to deep brain or neuromuscular tissue, there are diverse targets for electrical stimulation. Even though commercial systems are available, we state the need for a low-cost, high precision, functional, and modular (hardware, firmware, and software) current stimulation system with the capacity to generate stable and complex waveforms for pre-clinical research. The system presented in this study is a USB controlled 4-channel modular current stimulator that can be expanded and generate biphasic arbitrary waveforms with 16-bit resolution, high temporal precision (μs), and passive charge balancing: the NES STiM (Neuro Electronic Systems Stimulator). We present a detailed description of the system’s structural design, the controlling software, reliability test, and the pre-clinical studies [deep brain stimulation (DBS) in hemi-PD rat model] in which it was utilized. The NES STiM has been tested with MacOS and Windows operating systems. Interfaces to MATLAB source codes are provided. The system is inexpensive, relatively easy to build and can be assembled quickly. We hope that the NES STiM will be used in a wide variety of neurological applications such as Functional Electrical Stimulation (FES), DBS and closed loop neurophysiological research.

Structured illumination imaging with quasi-periodic patterns.

Structured illumination microscopy (SIM) is a well-established method for optical sectioning and super-resolution. The core of structured illumination is using a periodic pattern to excite image signals. This work reports a method for estimating minor pattern distortions from the raw image data and correcting these distortions during SIM image processing. The method was tested with both simulated and experimental image data from two-photon Bessel light-sheet SIM. The results proves the method is effective in challenging situations, where strong scattering background exists, signal-to-noise ratio (SNR) is low and the sample structure is sparse. Experimental results demonstrate restoring synaptic structures in deep brain tissue, despite the presence of strong light scattering and tissue-induced SIM pattern distortion.

Glutathione Peroxidase-Activatable Two-Photon Ratiometric Fluorescent Probe for Redox Mechanism Research in Aging and Mercury Exposure Mice Models.

Solid evidence confirms that glutathione peroxidase (GPx) is a kind of vital protease in the first-line antioxidant defense system and participates in regulation of redox homeostasis as well as the pentose phosphate pathway. However, the current methods cannot achieve real-time and in situ visualization studies of GPx. In addition, GPx is highly reactive and susceptible to external interference, and there is rare research for exploring the roles of GPx under environmental factor exposure. Herein, we report a novel two-photon ratiometric fluorescent probe (TP-SS) for GPx detection for the first time. Using TP-SS, we explore the reversible catalytic cycle and the antioxidant mechanisms of GPx/GSH redox pool in aging and mercury exposure models. We detect the concentration fluctuation of GPx in aging and mercury exposure mice models. Also, we perform GPx detection in deep brain tissue and the imaging depth up to 100 μm. We believe that the novel two-photon ratiometric fluorescent probe TP-SS can facilitate the development of GPx-targeting tools and offer great advances in exploring the physiological/pathological functions of GPx.

Label fusion method combining pixel greyscale probability for brain MR segmentation

Multi-atlas-based segmentation (MAS) methods have demonstrated superior performance in the field of automatic image segmentation, and label fusion is an important part of MAS methods. In this paper, we propose a label fusion method that incorporates pixel greyscale probability information. The proposed method combines the advantages of label fusion methods based on sparse representation (SRLF) and weighted voting methods using patch similarity weights (PSWV) and introduces pixel greyscale probability information to improve the segmentation accuracy. We apply the proposed method to the segmentation of deep brain tissues in challenging 3D brain MR images from publicly available IBSR datasets, including images of the thalamus, hippocampus, caudate, putamen, pallidum and amygdala. The experimental results show that the proposed method has higher segmentation accuracy and robustness than the related methods. Compared with the state-of-the-art methods, the proposed method obtains the best putamen, pallidum and amygdala segmentation results and hippocampus and caudate segmentation results that are similar to those of the comparison methods.

Real‐Time In Situ Holographic Optogenetics Confocally Unraveled Sculpting Microscopy

AbstractTwo‐photon (2P) optogenetic stimulation is currently the only method for precise, fast, and non‐invasive cellular excitation deep inside brain tissue; it is typically combined with holographic wavefront‐shaping techniques to generate distributed light patterns and target them to multiple specific cells in the brain. During propagation in the brain, these light patterns undergo severe distortion, mainly due to scattering, which leads to a discrepancy between the desired and actual light distribution. However, despite its importance, measurement of these tissue‐induced distortions and their effects on the light patterns has yet to be demonstrated in situ. To this end, holographic optogenetics confocally unraveled sculpting (HOCUS), a system for real‐time in situ evaluation of holographic light patterns, based on confocally descanning the stimulation light's reflection from the brain, is developed. HOCUS measures both tissue and wave propagation properties and enables the real‐time measurement and correction of the dimensions and positions of holographic spots relative to neurons targeted for stimulation. It can also be used to measure tissue attenuation length, and thus should facilitate future attempts to optimize the generated hologram to pre‐compensate for tissue‐induced distortions, thereby improving the reliability of 2P holographic stimulation experiments.

Lymphatic clearance is the main drainage route of lamotrigine-loaded micelles following delivery to the brain.

This study aimed to investigate the clearance pathways of lamotrigine (LTG)-loaded micelles by intranasal administration and intracerebral injection in the brain and whether nanoparticles can induce the inflammation promoted by interleukin-6 (IL-6), accelerating the phagocytosis of drug particles in the brain and drainage through lymphatics. The drug concentrations in the deep cervical lymph node, superficial cervical lymph node, brain tissues and jugular vein, the pharmacokinetic parameters, and the concentrations of IL-6 in deep cervical lymph node and brain tissues were investigated following UPLC/MS, DAS3.0, ELISA statistically analysed. The AUC0- t of deep cervical lymph node after intranasal and intracerebral injection was 1.93, 2.77, 1.34 times and 3.06, 16.4, 3.34 times higher compared with the superficial cervical lymph node, jugular vein and brain tissue, respectively. After intranasal administration of lamotrigine-loaded micelles for 30min, the IL-6 concentrations in deep cervical lymph node and brain tissue were significantly increased (P<0.05). These results suggested that lamotrigine micelles were primarily cleared from the brain by lymphatics rather than blood clearance. Also, the nanoparticle induced the increase in IL-6 level after entering the brain suggested that nanoparticles might induce the inflammation promoted by IL-6 in the brain, accelerating the clearance of drug particles in the brain and drainage through lymphatics.

Influence of extracerebral layers on estimates of optical properties with continuous wave near infrared spectroscopy: analysis based on multi-layered brain tissue architecture and Monte Carlo simulation

Continuous wave near-infrared spectroscopy (CW-NIRS) can be used to measure cerebral activity because it is noninvasive, simple and portable. However, the performance of the continuous wave near-infrared spectroscopy is distorted by the presence of extracerebral layer. Change of optical parameters in gray matter layer will then be inappropriately converted into the brain activity response. In the current study, a five-layer structure model constitute of scalp, skull, cerebrospinal fluid, gray matter and white matter, have been applied to fabricate human brain tissue. The phantom is made by the mixture of the Intralipid, India ink and agar. The optical parameters of gray matter layer can be flexibly adjusted to simulate the change of the deep brain tissue. The near infrared optical measurement system was designed to detect the changes in the absorption coefficients of the gray matter and quantitative analyze the influence of the extracerebral layers. Monte Carlo technique for the equivalent multi-layered brain tissue models is then performed to compensate partial volume effect introduced by the extracerebral layers. The results of the experiments suggested that the extracerebral layers influence the measurement and the influence of the extracerebral layers can be suppressed by correcting partial volume effect using Monte Carlo simulations.

Laser speckle contrast imaging of blood flow in the deep brain using microendoscopy.

Poor blood flow circulation can occur in the subcortical regions of the brain in many brain diseases. However, the limitations of light penetration imaging techniques hinder the detection of blood flow in deep brain tissues in vivo. Hence, in this Letter, we present a gradient index lens-based laser speckle contrast imaging system for time-lapse blood flow detection in subcortical regions of the brain. We monitored the hemodynamic changes in the thalamus of mouse models of acute hypoxia and transient middle cerebral artery occlusion as a proof of concept for practical applications.

Optical and thermal simulations for the design of optodes for minimally invasive optogenetics stimulation or photomodulation of deep and large cortical areas in non-human primate brain

The use of optogenetics or photobiomodulation in non-human primate (NHP) requires the ability to noninvasively stimulate large and deep cortical brain tissues volumes. In this context, the optical and geometrical parameters of optodes are critical. Methods and general guidelines to optimize these parameters have to be defined. Objective. We propose the design of an optode for safe and efficient optical stimulation of a large volume of NHP cortex, down to 3–5 mm depths without inserting fibers into the cortex. Approach. Monte Carlo simulations of optical and thermal transport have been carried out using the Geant4 application for tomographic emission (GATE) platform. Parameters such as the fiber diameter, numerical aperture, number of fibers and their geometrical arrangement have been studied. Optimal hardware parameters are proposed to obtain homogeneous fluence above the fluence threshold for opsin activation without detrimental thermal effects. Main results. The simulations show that a large fiber diameter and a large numerical aperture are preferable since they allow limiting power concentration and hence the resulting thermal increases at the brain surface. To obtain a volume of 200–500 mm3 of brain tissues receiving a fluence above the opsin activation threshold for optogenetics or below a phototocixity threshold for photobiomodulation, a 4 fibers configuration is proposed. The optimal distance between the fibers was found to be 4 mm. A practical implementation of the optode has been performed and the corresponding fluence and thermal maps have been simulated. Significance. The present study defines a method to optimize the design of optode and the choice of stimulation parameters for optogenetics and more generally light delivery to deep and large volumes of tissues in NHP brain with a controlled irradiance dosimetry. The general guidelines are the use of silica fibers with a large numerical aperture and a large diameter. The combination of several fibers is required if large volumes need to be stimulated while avoiding thermal effects.