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Review

Optical Navigation, Fluorescence-Guided Surgery, and Artificial Light Technologies in Modern Neurosurgery: Advancing Precision Surgical Visualization

by
Dimitar Slavkov
1,
Svetoslava Troyanova-Slavkova
2,3,* and
Petranka Troyanova
4
1
Department of Neurosurgery, “Tsaritsa Yoanna” University Hospital, 1527 Sofia, Bulgaria
2
Department of Dermatoncology, University Specialized Hospital for Active Treatment in Oncology “Prof. Iv. Chernozemski”, 1756 Sofia, Bulgaria
3
Department of Dermatology and Allergology, Medical University Pleven, 5800 Pleven, Bulgaria
4
Department of Oncology, “Tsaritsa Yoanna” University Hospital, 1527 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Lights 2026, 2(3), 6; https://doi.org/10.3390/lights2030006
Submission received: 28 May 2026 / Revised: 20 July 2026 / Accepted: 27 July 2026 / Published: 28 July 2026
Review Reports Versions Notes

Abstract

Technological advances in optical imaging and artificial light technologies have substantially transformed modern neurosurgical practice by improving intraoperative visualization and surgical precision. This narrative review evaluates current applications of fluorescence-guided surgery, optical navigation systems, near-infrared imaging, augmented visualization platforms, and artificial intelligence-assisted intraoperative imaging in neurosurgery. Particular attention is given to clinically established fluorophores, including 5-aminolevulinic acid, fluorescein sodium, and indocyanine green, which are increasingly used for tumor delineation, vascular assessment, and real-time tissue perfusion analysis. Emerging technologies such as Raman spectroscopy, multispectral imaging, holographic navigation, and nerve-specific fluorescent probes are also discussed in the context of precision and minimally invasive neurosurgery. Current evidence demonstrates that advanced optical systems improve surgical orientation, maximize extent of resection, and support preservation of critical neurovascular structures, particularly in neuro-oncology, vascular neurosurgery, and skull base surgery. However, limitations related to fluorescence specificity, standardization, cost, and technological accessibility remain significant challenges. The continued integration of multimodal optical imaging, computational navigation, and AI-assisted visualization is expected to further enhance intraoperative decision-making, surgical safety, and postoperative outcomes, contributing to the future development of precision image-guided neurosurgery.

1. Introduction

Maximal safe resection remains one of the principal goals of modern neurosurgery, particularly in neuro-oncology and cerebrovascular surgery, where surgical precision directly influences neurological outcomes, progression-free survival, and overall patient prognosis [1]. Despite major advances in microsurgical techniques, conventional white-light operative microscopy still provides limited ability to distinguish pathological tissue from normal brain parenchyma, especially at infiltrative tumor margins or within anatomically complex regions. These limitations have driven the rapid development of advanced optical imaging and artificial light technologies designed to improve intraoperative visualization, surgical orientation, and tissue discrimination [2].
Over the past two decades, fluorescence-guided surgery (FGS) has emerged as a major innovation in precision neurosurgery. Fluorophores such as 5-aminolevulinic acid (5-ALA), fluorescein sodium (FNa), and indocyanine green (ICG) are increasingly used for real-time visualization of tumor tissue, vascular anatomy, and tissue perfusion [3]. Clinical studies have demonstrated that these technologies may improve the extent of resection while reducing injury to eloquent cortical regions and critical neurovascular structures. Novel nerve-specific fluorophores have shown promising potential for improving functional preservation through enhanced visualization of peripheral and autonomic neural structures. Nevertheless, important controversies remain regarding fluorescence specificity, variability in signal interpretation, limited penetration depth, and the lack of standardized intraoperative imaging protocols [4].
Simultaneously, advances in optical neuronavigation, high-definition exoscopic systems, augmented and mixed reality interfaces, and holographic visualization platforms have significantly enhanced intraoperative spatial orientation and surgical workflow. Emerging technologies such as Raman spectroscopy, hyperspectral imaging, confocal laser endomicroscopy, and machine learning-assisted image analysis further support the transition from anatomy-based surgery toward biologically informed and data-driven precision neurosurgery [5].
Although many of these technologies have demonstrated encouraging clinical utility, their integration into routine neurosurgical practice remains associated with technological, economic, and regulatory challenges. Furthermore, the rapid evolution of artificial intelligence-assisted imaging and multimodal optical systems continues to redefine the role of intraoperative visualization in surgical decision-making.
The aim of this narrative review is to summarize current advances in fluorescence-guided surgery, optical navigation, and artificial light technologies in neurosurgery, with particular emphasis on their underlying principles, clinical applications, limitations, and future perspectives. Collectively, these technologies are shaping the future of precision image-guided neurosurgery and may substantially improve surgical safety, resection accuracy, and postoperative neurological outcomes.

2. Materials and Methods

This study was designed as a narrative review focusing on the current applications, technological developments, and future perspectives of fluorescence-guided surgery, optical navigation, and artificial light technologies in modern neurosurgery. The review particularly addressed the role of advanced optical imaging systems in neuro-oncology, vascular neurosurgery, skull base surgery, stereotactic procedures, and intraoperative functional preservation.
A comprehensive literature search was conducted using publicly accessible scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar. Relevant articles published primarily between 2020 and 2025 were reviewed, with additional landmark historical studies included where necessary to provide scientific context. Search terms included combinations of “fluorescence-guided surgery”, “5-aminolevulinic acid”, “fluorescein sodium”, “indocyanine green”, “optical navigation”, “augmented reality”, “mixed reality”, “Raman spectroscopy”, “hyperspectral imaging”, “confocal laser endomicroscopy”, “artificial intelligence”, “neurosurgery”, “precision neurosurgery”, and “intraoperative imaging”.
Eligible publications included clinical studies, randomized controlled trials, prospective and retrospective studies, technical reports, translational experimental investigations, and relevant review articles addressing optical visualization technologies in neurosurgery. Studies focusing exclusively on non-neurosurgical applications were excluded unless they provided important methodological or technological insights applicable to neurosurgical practice. The retrieved publications were evaluated according to their scientific relevance, methodological quality, level of clinical evidence, and contribution to the field of optical neurosurgery. Particular emphasis was placed on randomized controlled trials, prospective clinical studies, systematic reviews, meta-analyses, and consensus recommendations whenever available. Landmark studies were included to provide historical context, whereas recent publications were incorporated to reflect the latest technological developments. Owing to the narrative nature of this review, no formal risk-of-bias assessment or quantitative meta-analysis was performed.
As this work represents a narrative review based exclusively on previously published studies, no human participants, patient data, or animal experiments were directly involved, and institutional review board approval was not required. No unpublished datasets were generated or analyzed during the preparation of this manuscript.

3. Results

3.1. Principles of Optical Imaging in Neurosurgery

Optical imaging technologies rely on the interaction between light and biological tissues to generate contrast between normal and pathological structures. Fluorescence imaging represents the most widely adopted optical modality in neurosurgery. In fluorescence-guided surgery, fluorophores absorb light at specific excitation wavelengths and subsequently emit light at longer wavelengths, enabling selective visualization of target tissues [6]. Each fluorophore is characterized by a specific excitation and emission spectrum, which determines the optical filters required for intraoperative visualization. For example, 5-aminolevulinic acid-induced protoporphyrin IX (PpIX) is excited by blue-violet light (approximately 375–440 nm) and emits red fluorescence with a peak around 635 nm. Fluorescein sodium is excited by blue light (460–500 nm) and emits yellow-green fluorescence at approximately 540–690 nm, whereas indocyanine green (ICG) is excited in the near-infrared range (approximately 780–805 nm) and emits fluorescence around 820–835 nm. These spectral characteristics determine their respective clinical applications and imaging systems [6].
The effectiveness of fluorescence imaging depends on several parameters, including excitation and emission spectra, tissue autofluorescence, fluorophore specificity, optical penetration depth, and signal-to-background ratio. Near-infrared (NIR) fluorophores have gained increasing attention because NIR light demonstrates greater tissue penetration and reduced autofluorescence compared with visible-light fluorophores.
Different tissue types exhibit distinct optical properties based on their cellular composition, vascularity, metabolic activity, and molecular structure. Besides fluorescence emission, optical navigation also relies on the detection of backscattered light originating from tissue scattering. White-light reflectance and backscattering are primarily influenced by cellular density, myelin content, vascularization, and tissue architecture. Tumor tissue generally demonstrates altered scattering properties compared with normal brain parenchyma owing to increased cellularity, edema, necrosis, and microvascular proliferation. Modern hyperspectral and multispectral imaging systems combine reflected light and fluorescence signals to improve tissue discrimination. Malignant tissues often demonstrate altered metabolic pathways, abnormal vascular permeability, and increased cellular proliferation, which can facilitate selective accumulation of fluorescent agents and enhance optical contrast during surgery [7].
In fluorescence-guided procedures, dedicated optical filters integrated into surgical microscopes or exoscopic systems isolate emitted fluorescence signals from background illumination, thereby enabling real-time visualization of pathological tissue. The intensity and distribution of fluorescence are influenced by fluorophore concentration, tissue oxygenation, pH, blood content, and local microenvironmental factors, all of which may affect intraoperative image interpretation [8]. The tumor microenvironment also influences fluorescence characteristics. Tumor-associated macrophages (TAMs) and tumor-associated microglia constitute a substantial proportion of the glioma microenvironment and contribute to blood–brain barrier disruption, extracellular matrix remodeling, and inflammatory signaling. Although these immune cells do not directly produce clinically relevant fluorescence, they may indirectly modify fluorophore accumulation through alterations in vascular permeability, regional metabolism, tissue oxygenation, and local inflammatory responses, thereby influencing fluorescence intensity and signal heterogeneity [7].
Recent advances in optical engineering have enabled the development of multispectral and hyperspectral imaging systems capable of simultaneously detecting multiple wavelengths of reflected or emitted light. These technologies provide additional biochemical and functional information beyond conventional white-light imaging, facilitating improved tissue characterization and intraoperative decision-making. Similarly, fluorescence lifetime imaging (FLIM) analyzes the temporal decay of fluorescence signals, allowing differentiation between tissue types based on the molecular microenvironment rather than fluorescence intensity alone [9].
Modern optical systems increasingly combine fluorescence imaging with multimodal visualization technologies, including spectroscopy, endomicroscopy, augmented reality overlays, and computational image processing. Raman spectroscopy, for example, identifies tissues according to their unique molecular vibrational signatures, while confocal laser endomicroscopy enables real-time microscopic imaging at near-histological resolution during surgery. Furthermore, integration of artificial intelligence and machine learning algorithms into optical imaging platforms has improved automated tissue classification, fluorescence quantification, and intraoperative image analysis [10].
Collectively, these technologies aim to provide real-time anatomical, functional, and molecular information during surgery while minimizing disruption of surgical workflow. The ongoing convergence of advanced optical imaging, computational analysis, and intraoperative navigation is progressively transforming neurosurgery toward a highly precise, data-driven, and minimally invasive discipline.

3.2. Fluorescence-Guided Surgery in Neurosurgery

3.2.1. 5-Aminolevulinic Acid (5-ALA)

5-ALA represents the most established fluorophore in neurosurgical oncology. As a precursor in heme biosynthesis, 5-ALA induces intracellular accumulation of protoporphyrin IX (PpIX), a photosensitive molecule that preferentially accumulates in malignant glioma cells. Under blue-violet light excitation, PpIX emits red fluorescence, enabling intraoperative visualization of tumor tissue [11]. PpIX fluorescence is generally strongest in WHO grade 4 gliomas, intermediate in WHO grade 3 tumors, and substantially weaker or absent in most diffuse low-grade gliomas because of lower metabolic activity and reduced intracellular PpIX accumulation. Visible fluorescence therefore correlates, although imperfectly, with tumor grade and cellular proliferation.
Clinical studies have consistently demonstrated that 5-ALA improves gross total resection rates in high-grade glioma surgery and significantly increases progression-free survival compared with conventional white-light surgery. Its ability to identify infiltrative tumor margins has made it a cornerstone of fluorescence-guided glioma surgery. Recent investigations have expanded the role of 5-ALA beyond glioblastoma surgery. Applications have been explored in metastatic brain tumors, meningiomas, spinal ependymomas, pituitary adenomas, and pediatric tumors. Furthermore, integration of 5-ALA with photodynamic therapy (PDT) has demonstrated promising synergistic antitumor effects through selective generation of reactive oxygen species within malignant cells [12].
Despite its advantages, 5-ALA has important limitations. False-positive and false-negative fluorescence remain significant challenges, particularly in low-grade gliomas and deep-seated lesions. Variability in PpIX accumulation, limited tissue penetration of blue light, and subjective fluorescence interpretation may compromise resection accuracy. Economic considerations, preoperative administration requirements, and lack of standardization in dosing and timing also limit widespread implementation [13]. Fluorescence lifetime imaging (FLIM) has recently emerged as a complementary technique capable of differentiating tissue based on fluorescence decay rather than fluorescence intensity alone. Experimental studies suggest that fluorescence lifetime parameters may differ between high-grade gliomas, low-grade gliomas, necrotic tissue, and normal brain, potentially improving intraoperative tissue characterization independent of fluorophore concentration. However, clinical implementation remains limited [12]. Despite its advantages, 5-ALA has important limitations. False-positive and false-negative fluorescence remain significant challenges, particularly in low-grade gliomas and deep-seated lesions. Variability in PpIX accumulation, limited tissue penetration of blue light, and subjective fluorescence interpretation may compromise resection accuracy. Economic considerations, preoperative administration requirements, and lack of standardization in dosing and timing also limit widespread implementation [14].
Several strategies have recently been proposed to improve fluorescence specificity. Quantitative fluorescence imaging aims to objectively measure fluorophore concentration rather than relying solely on subjective visual assessment. Spectroscopic analysis enables discrimination between true PpIX fluorescence and tissue autofluorescence, whereas fluorescence lifetime imaging (FLIM) provides contrast based on fluorescence decay characteristics that are less affected by fluorophore concentration or illumination intensity [15]. In addition, artificial intelligence-based image analysis and machine learning algorithms have shown promising results in reducing observer variability and improving intraoperative tissue classification. Finally, the development of tumor-targeted molecular fluorophores and multimodal imaging approaches combining fluorescence with Raman spectroscopy or hyperspectral imaging may further enhance specificity in future clinical practice. Although none of these approaches has yet completely overcome the problem of false-positive and false-negative fluorescence, they represent important steps toward more objective, quantitative, and biologically specific fluorescence-guided neurosurgery [16].
Nevertheless, 5-ALA remains the most clinically validated tumor-specific fluorophore in neurosurgery and continues to serve as the reference standard for fluorescence-guided glioma surgery [17].

3.2.2. Fluorescein Sodium

Fluorescein sodium (FNa) is a water-soluble fluorescent dye that accumulates in regions with blood–brain barrier disruption. Unlike 5-ALA, FNa does not selectively target tumor metabolism but instead distributes nonspecifically within tumor microenvironments [14]. Because fluorescein sodium accumulates in areas of blood–brain barrier disruption rather than within tumor cells themselves, fluorescence intensity correlates primarily with vascular permeability instead of intrinsic tumor biology. Consequently, strong fluorescence may also be observed in regions of inflammation, treatment-related changes, or surgical manipulation [18].
When visualized through microscope-integrated yellow filters, FNa provides enhanced delineation of malignant tissue and facilitates real-time intraoperative orientation. Its rapid uptake, low cost, and broad applicability have contributed to increasing use in glioma surgery, meningioma resection, spinal tumor procedures, and pituitary surgery [18].
Recent developments integrating FNa with confocal laser endomicroscopy have enabled real-time intraoperative histological imaging. Systems such as confocal fluorescence microscopy platforms provide optical biopsies capable of distinguishing tumor tissue from normal brain parenchyma during surgery. Artificial intelligence-based image processing algorithms are also being explored to standardize fluorescence interpretation and improve tissue classification [19].
Despite these advantages, FNa remains limited by nonspecific accumulation in inflammatory tissue, edema, and surgically manipulated regions, which may generate false-positive fluorescence. Concerns regarding allergic reactions, toxicity, and off-label neurosurgical use persist. Additionally, visible-spectrum fluorescence limits tissue penetration compared with near-infrared fluorophores [20].
Future research will likely focus on improving fluorescence standardization, optimizing administration protocols, and integrating AI-assisted fluorescence quantification into clinical workflows.

3.2.3. Indocyanine Green (ICG)

Indocyanine green is a near-infrared fluorophore widely utilized in vascular neurosurgery. Following intravenous administration, ICG binds plasma proteins and remains largely confined to the vascular compartment, enabling real-time visualization of blood flow and tissue perfusion [8]. The near-infrared optical window allows deeper tissue penetration (up to several millimeters) and lower tissue autofluorescence than visible-light fluorophores, making ICG particularly suitable for vascular imaging and perfusion assessment, although its lack of tumor specificity limits its application in fluorescence-guided tumor resection [21].
ICG angiography has become an essential intraoperative tool during aneurysm clipping, arteriovenous malformation (AVM) surgery, bypass procedures, and skull base vascular interventions. Microscope-integrated ICG systems provide dynamic assessment of vessel patency, aneurysm occlusion, and cerebral perfusion without interrupting surgical workflow [22].
The introduction of second-window ICG (SWIG) techniques has expanded the use of ICG into neuro-oncology. High-dose delayed ICG administration enables enhanced visualization of gadolinium-enhancing tumors, including glioblastomas, metastases, meningiomas, and skull base lesions. ICG additionally benefits from near-infrared optical properties, which allow deeper tissue penetration and reduced autofluorescence compared with visible-spectrum fluorophores. Emerging applications include nanoparticle-mediated photothermal therapy, shortwave infrared imaging, and theranostic platforms combining imaging and targeted therapy [23].
However, ICG also has limitations, including restricted visualization outside the microscopic field, limited quantitative perfusion analysis, and the need for specialized imaging equipment. Its short plasma half-life often requires repeated administration during lengthy procedures [23].
The principal fluorophores currently used in fluorescence-guided neurosurgery differ substantially in their mechanisms of action, optical characteristics, clinical indications, and reported surgical outcomes. A comparative summary of their representative clinical performance and major limitations is presented in Table 1.
Although fluorescence provides valuable real-time intraoperative guidance, it should not be interpreted in isolation. Awareness of the limitations and potential sources of error associated with each fluorophore is essential, and fluorescence findings should always be integrated with neuronavigation, preoperative MRI, anatomical landmarks, and the surgeon’s intraoperative judgment to optimize surgical decision-making [19].

3.2.4. Emerging Nerve-Specific Optical Probes

Preservation of functional neural structures represents a major challenge in modern neurosurgery. Consequently, new generations of nerve-specific fluorescent probes have emerged to reduce iatrogenic nerve injury and improve functional outcomes.
  • GE3126
GE3126 is a fluorescent nerve-targeting agent designed to bind myelin-associated structures and improve visualization of peripheral nerves during surgery. Experimental studies have demonstrated rapid and high-contrast nerve visualization under fluorescence guidance, particularly in minimally invasive procedures [24].
Potential applications include skull base surgery, peripheral nerve surgery, and autonomic nerve preservation. However, limitations related to myelin specificity, false-positive fluorescence, and the requirement for blue-light illumination remain important obstacles for clinical translation [25].
  • NP41 and HNP-401
NP41 is a fluorescent peptide probe targeting laminin-associated extracellular matrix components surrounding neural tissue. Unlike traditional neural tracers, NP41 labels multiple neural structures simultaneously after systemic administration, enabling visualization of both myelinated and unmyelinated nerves. Preclinical studies have demonstrated improved nerve-to-background contrast, enhanced visualization of small autonomic nerve branches, and detection of degenerated or transected nerves. Its successor, HNP-401, demonstrates even greater signal intensity and improved specificity in human tissue models [26].
These emerging probes may become particularly valuable in skull base surgery, peripheral nerve reconstruction, spinal procedures, and functional neurosurgery, where preservation of neural integrity is essential.

3.3. Optical Navigation and Augmented Visualization

Modern neurosurgery increasingly depends on advanced navigation systems capable of integrating multimodal imaging datasets into real-time surgical workflows. Optical neuronavigation systems utilize infrared tracking cameras, stereotactic guidance, and image-registration algorithms to improve spatial orientation during surgery.
Recent advances in augmented reality (AR), mixed reality (MR), and holographic visualization have further expanded the capabilities of surgical navigation. Platforms such as HoloSNS, HoloDBS, and HoloSEEG integrate patient-specific MRI data, tractography, stereotactic trajectories, and computational brain models into immersive holographic environments [27].
These technologies allow surgeons to interact with three-dimensional reconstructions of neural anatomy, improving understanding of spatial relationships and facilitating trajectory planning in deep brain stimulation (DBS), stereoelectroencephalography (SEEG), and skull base surgery.
Exoscopic systems additionally provide high-definition digital visualization with improved ergonomics and expanded visualization angles compared with conventional microscopy. Integration of AR overlays into exoscopic platforms may further enhance intraoperative orientation and surgical precision [28].
Although these technologies remain relatively expensive and technically demanding, they represent a major step toward intelligent image-guided neurosurgery.

3.4. Artificial Intelligence and Computational Optical Neurosurgery

Artificial intelligence is emerging as a transformative component of intraoperative optical imaging. One of the major limitations of fluorescence-guided surgery is the subjective interpretation of fluorescence intensity and tissue contrast. Machine learning algorithms may overcome this limitation through automated tissue classification and quantitative fluorescence analysis [29].
Current AI-assisted systems are being developed for intraoperative tumor segmentation, fluorescence signal quantification, Raman spectroscopy analysis, optical biopsy interpretation, perfusion assessment, predictive radiomics, and automated surgical guidance. Recent advances in deep learning, particularly convolutional neural networks (CNNs) and transformer-based architectures, have further expanded these capabilities by enabling real-time intraoperative image analysis. Through the integration of fluorescence imaging with neuronavigation, operative microscopy, preoperative magnetic resonance imaging, and spectroscopic data, these algorithms can continuously analyze imaging information during surgery, assisting with tumor boundary delineation, automated tissue segmentation, fluorescence quantification, and the identification of infiltrative tumor margins. Importantly, these systems are intended to support rather than replace the surgeon’s intraoperative decision-making by providing objective image interpretation and highlighting regions that may warrant closer inspection.
Raman spectroscopy combined with machine learning has shown particular promise for differentiating tumor tissue from normal brain tissue based on molecular signatures. Similarly, hyperspectral imaging and confocal laser endomicroscopy integrated with deep learning algorithms may enable near-real-time histopathological diagnosis during surgery [30].
Although several emerging optical technologies have demonstrated considerable promise in preclinical and early clinical studies, their routine implementation in neurosurgical practice remains at different stages of clinical translation. Raman spectroscopy is currently the closest to widespread clinical adoption, supported by growing evidence demonstrating high diagnostic accuracy for intraoperative tissue characterization and the recent development of rapid, clinically applicable imaging platforms. In contrast, holographic navigation systems and nerve-specific fluorescent probes have shown encouraging results in feasibility and early clinical studies but still require larger prospective multicenter trials, regulatory approval, workflow standardization, and cost-effective integration before becoming part of routine neurosurgical practice. Continued advances in optical instrumentation, artificial intelligence, and image-guided navigation are expected to accelerate their clinical translation in the coming years [5].
Table 1. Comparative characteristics and representative clinical outcomes of the principal fluorophores used in fluorescence-guided neurosurgery.
Table 1. Comparative characteristics and representative clinical outcomes of the principal fluorophores used in fluorescence-guided neurosurgery.
FluorophoreSensitivitySpecificityTissue PenetrationExcitation/Emission Wave
Length		Mechanism of FluorescencePrincipal Clinical IndicationRepresentative Clinical OutcomesMain LimitationsKey References
5-Amino-levulinic acid
(5-ALA/PpIX)		High in HGG (>85%)Highest tumor specificityLow (≈1–2 mm)405 nm/635 nmIntracellular accumulation of protoporphyrin IX through the heme biosynthesis pathwayHigh-grade gliomasGross total resection (GTR): 65% vs. 36% with conventional white-light surgery; 6-month progression-free survival (PFS): 41% vs. 21%Limited sensitivity in low-grade gliomas; false-negative fluorescence; limited blue-light penetration; subjective fluorescence interpretationMazurek et al., 2025 [13];
Chen et al., 2025 [17];
Fluorescein sodium (FNa)HighModerateModerate460–500 nm/540–690 nmPassive accumulation in areas of blood–brain barrier disruptionHigh-grade gliomas, brain metastases, meningiomasReported GTR rates of approximately 75–85% in contemporary clinical series; improved intraoperative visualization of tumor marginsNon-specific accumulation in edema, inflammation, and treatment-related tissue; false-positive fluorescenceChen et al., 2022 [18]; Brielmaier et al., 2025 [19]; Kogias et al., 2026 [30];
Indo-cyanine green
(ICG)		Excellent for vesselsHigh for vascular imaging; low for tumor specificityDeepest (near-infrared)780–805 nm/820–835 nmIntravascular near-infrared fluorophore binding to plasma proteinsCerebrovascular surgery (aneurysms, AVMs, bypass); second-window ICG (SWIG) in neuro-oncologyIntraoperative vessel patency assessment > 95%;
improved identification of residual aneurysm filling and bypass patency; SWIG enhances visualization of contrast-enhancing tumors		Limited tumor specificity; specialized NIR imaging required; short plasma half-lifeGhosh et al., 2023 [21]; Calabrese et al., 2025 [23]
To facilitate comparison of the principal optical imaging modalities discussed in this review, their main characteristics, advantages, limitations, and current clinical applications are summarized in Table 2.
Evidence regarding long-term patient outcomes remains strongest for fluorescence-guided resection of high-grade gliomas, particularly with 5-ALA. The landmark randomized trial demonstrated improved complete resection rates and six-month progression-free survival but did not establish a significant overall survival advantage. More recent observational studies have reported favorable survival associations; however, a 2026 systematic review and meta-analysis found that the apparent overall survival benefit was attenuated and no longer statistically significant after adjustment for major prognostic factors. These findings suggest that fluorescence guidance contributes primarily by facilitating maximal safe resection, with any long-term benefit likely mediated through the extent of resection rather than through an independent effect of the imaging technology itself [15]. For fluorescein sodium, indocyanine green, Raman spectroscopy, hyperspectral imaging, confocal laser endomicroscopy, and other emerging optical approaches, current evidence predominantly concerns diagnostic accuracy, surgical precision, and short-term procedural outcomes, while robust data demonstrating independent long-term survival benefits remain limited.

4. Limitations and Current Challenges

Despite substantial progress, several limitations continue to restrict the widespread adoption of advanced optical technologies in neurosurgery.
A major challenge remains the variability in fluorescence interpretation and the absence of universally accepted standardized protocols for fluorophore administration, imaging acquisition, and fluorescence threshold assessment. Tissue heterogeneity, edema, blood contamination, inflammation, and necrosis may substantially alter fluorescence intensity and reduce diagnostic specificity.
To minimize these sources of variability, several evidence-based recommendations and institutional protocols have been introduced for fluorescence-guided neurosurgery. Although internationally standardized operating procedures have not yet been fully established, current clinical practice follows several widely accepted principles. For 5-ALA-guided surgery, oral administration approximately three hours before induction of anesthesia remains the standard approach, whereas fluorescein sodium is typically administered intravenously after anesthesia induction using dedicated yellow microscope filters. Indocyanine green is generally injected immediately before vascular imaging because of its short intravascular half-life. Standardized intraoperative workflows also include the use of dedicated optical filter systems, optimization of operating room illumination, correlation of fluorescence findings with preoperative magnetic resonance imaging and neuronavigation, and systematic interpretation of fluorescence throughout tumor resection. Ongoing multicenter studies, quantitative fluorescence analysis, and artificial intelligence-assisted image processing are expected to further improve reproducibility and interinstitutional standardization [30].
Beyond technical limitations, the implementation of advanced optical technologies is also influenced by economic, infrastructural, and organizational considerations. The acquisition and maintenance of dedicated fluorescence imaging systems, high-performance operating microscopes, neuronavigation platforms, and computational infrastructure require substantial financial investment, which may limit accessibility, particularly in resource-constrained healthcare systems. Successful implementation additionally depends on specialized multidisciplinary training, standardized clinical workflows, and sufficient institutional case volume to maintain technical expertise. Consequently, these technologies are currently more readily integrated into tertiary referral centers and academic neurosurgical institutions than into smaller regional hospitals. Continued technological simplification, cost reduction, and broader dissemination of standardized imaging platforms are expected to improve accessibility and facilitate wider clinical adoption [31].
Furthermore, many optical imaging technologies still lack evidence from large multicenter randomized clinical trials demonstrating long-term improvements in patient outcomes. Regulatory approval for several fluorescent agents remains incomplete, and many applications continue to be performed off-label.
Additional technical limitations include restricted optical penetration depth, variability in quantitative fluorescence measurements across different imaging platforms, workflow disruption, and prolonged operative times, all of which require further technological refinement before routine implementation.

5. Future Perspectives

Many of the current challenges discussed in the previous section, including limited standardization, suboptimal fluorescence specificity, and insufficient interoperability between imaging platforms, are expected to be addressed through the convergence of multimodal optical imaging, artificial intelligence, computational modeling, and robotic technologies.
Emerging technologies under investigation include the following:
  • Hyperspectral imaging;
  • Fluorescence lifetime imaging (FLIM);
  • Optical coherence tomography (OCT);
  • Quantum-dot fluorophores;
  • Photoacoustic imaging;
  • Activatable molecular probes;
  • Nanoparticle-based theranostics;
  • Robotic fluorescence-guided surgery.
Beyond optical imaging alone, emerging biosensing technologies based on advanced nanomaterials are expanding the possibilities for intraoperative tissue characterization. In particular, graphene-enabled sensing platforms and metasurface-based biosensors have demonstrated promising preliminary results for highly sensitive brain tumor detection and may complement future optical imaging approaches through enhanced molecular sensing. Although these technologies remain at an early stage of clinical translation, continued advances in nanomaterials, biosensor engineering, and artificial intelligence-assisted signal analysis may further broaden the spectrum of image-guided neurosurgical diagnostics [32].
Multimodal systems capable of integrating fluorescence imaging, holographic navigation, AI-assisted tissue analysis, robotic assistance, and intraoperative navigation platforms are expected to improve interoperability, streamline surgical workflows, and ultimately create intelligent surgical ecosystems supporting personalized precision neurosurgery [33].
The development of targeted fluorophores with improved specificity, deeper tissue penetration, and multiplexed imaging capabilities may further enhance intraoperative discrimination between tumor tissue, functional cortex, vascular structures, and neural pathways [31].
Future operating rooms may evolve into highly integrated digital environments where optical imaging, computational analytics, and augmented visualization function synergistically to optimize surgical safety and neurological preservation. Selection of the optimal optical technology should be tailored to the specific neurosurgical pathology. At present, 5-ALA remains the preferred fluorophore for high-grade glioma surgery because of its tumor specificity, whereas fluorescein sodium provides a cost-effective alternative for lesions associated with blood–brain barrier disruption. Indocyanine green remains the gold standard for vascular neurosurgery and intraoperative perfusion assessment. Emerging multimodal approaches combining targeted fluorophores, fluorescence lifetime imaging, hyperspectral imaging, and artificial intelligence are expected to further improve precision across different tumor types and surgical indications.

6. Conclusions

Optical imaging and advanced light-based technologies have transformed contemporary neurosurgery by enabling real-time visualization of tumor biology, vascular anatomy, and functional neural structures. Fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA), fluorescein sodium, and indocyanine green has substantially improved intraoperative tumor delineation, vascular assessment, and the preservation of eloquent neurovascular structures, thereby enhancing surgical accuracy and supporting maximal safe resection.
Continued advances in optical navigation, computational imaging, and artificial intelligence are further expanding the capabilities of image-guided neurosurgery by providing increasingly objective and data-driven intraoperative decision support. At the same time, emerging optical technologies continue to broaden the spectrum of applications beyond tumor visualization toward comprehensive functional and molecular characterization of surgical targets.
Despite persistent challenges related to standardization, clinical validation, interoperability, and broad implementation, the current trajectory of technological development is highly encouraging. Ongoing progress in multimodal imaging, quantitative optical analysis, and intelligent surgical platforms is expected to improve reproducibility, facilitate clinical integration, and further optimize surgical workflows.
As these technologies continue to mature, their incorporation into routine neurosurgical practice is likely to enhance surgical safety, maximize therapeutic effectiveness, and support increasingly personalized neurosurgical care. Together, these advances are expected to play a pivotal role in shaping the next generation of precision image-guided neurosurgery.

Author Contributions

Conceptualization, D.S. and S.T.-S.; methodology, D.S.; software, P.T.; validation, D.S., S.T.-S. and P.T.; formal analysis, D.S. and P.T.; investigation, D.S. and S.T.-S.; resources, S.T.-S.; data curation, P.T.; writing—original draft preparation, D.S.; writing—review and editing, D.S., S.T.-S. and P.T.; visualization, P.T.; supervision, S.T.-S.; project administration, D.S.; funding acquisition, S.T.-S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Table 2. Comparison of the principal optical imaging modalities currently used in neurosurgery.
Table 2. Comparison of the principal optical imaging modalities currently used in neurosurgery.
Imaging ModalityMain PrincipleAdvantagesLimitationsPrincipal Clinical Applications
White-light microscopyConventional optical visualizationWidely available; familiar workflowLimited tumor contrastStandard microsurgery
5-ALA fluorescencePpIX fluorescenceHighest tumor specificity; improved GTRLimited in LGG; shallow penetrationHigh-grade gliomas
Fluorescein-guided imagingBBB disruptionSimple; inexpensive; broad tumor applicabilityLower specificityGliomas; metastases
ICG fluorescenceNear-infrared vascular fluorescenceExcellent vascular imaging; deep penetrationLimited tumor specificityAneurysms; AVMs; bypass
Raman spectroscopyMolecular fingerprintingLabel-free; high specificitySmall field of view; slower acquisitionTumor margin assessment
Hyperspectral imagingTissue spectral signaturesNon-contact; label-freeLarge datasets; computational demandTumor characterization
Confocal laser endomicroscopyCellular-resolution microscopyNear-histological detailLimited penetration; learning curveOptical biopsy
Optical coherence tomography (OCT)Low-coherence interferometryHigh-resolution structural imagingLimited penetration depthWhite matter and margin assessment
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Slavkov, D.; Troyanova-Slavkova, S.; Troyanova, P. Optical Navigation, Fluorescence-Guided Surgery, and Artificial Light Technologies in Modern Neurosurgery: Advancing Precision Surgical Visualization. Lights 2026, 2, 6. https://doi.org/10.3390/lights2030006

AMA Style

Slavkov D, Troyanova-Slavkova S, Troyanova P. Optical Navigation, Fluorescence-Guided Surgery, and Artificial Light Technologies in Modern Neurosurgery: Advancing Precision Surgical Visualization. Lights. 2026; 2(3):6. https://doi.org/10.3390/lights2030006

Chicago/Turabian Style

Slavkov, Dimitar, Svetoslava Troyanova-Slavkova, and Petranka Troyanova. 2026. "Optical Navigation, Fluorescence-Guided Surgery, and Artificial Light Technologies in Modern Neurosurgery: Advancing Precision Surgical Visualization" Lights 2, no. 3: 6. https://doi.org/10.3390/lights2030006

APA Style

Slavkov, D., Troyanova-Slavkova, S., & Troyanova, P. (2026). Optical Navigation, Fluorescence-Guided Surgery, and Artificial Light Technologies in Modern Neurosurgery: Advancing Precision Surgical Visualization. Lights, 2(3), 6. https://doi.org/10.3390/lights2030006

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