Patient-Specific Vascular Flow Phantom for MRI- and Doppler Ultrasound Imaging.

OBJECTIVE: Intraoperative Doppler ultrasound imaging of human brain vasculature is an emerging neuro-imaging modality that offers vascular brain mapping with unprecedented spatiotemporal resolution. At present, however, access to the human brain using Doppler Ultrasound is only possible in this intraoperative context, posing a significant challenge for validation of imaging techniques. This challenge necessitates the development of realistic flow phantoms outside of the neurosurgical operating room as external platforms for testing hardware and software. An ideal ultrasound flow phantom should provide reference-like values in standardized topologies such as a slanted pipe, and allow for measurements in structures closely resembling vascular morphology of actual patients. Additionally, the phantom should be compatible with other clinical cerebrovascular imaging modalities. To meet these criteria, we developed and validated a versatile, multimodal MRI- and ultrasound Doppler phantom. METHODS: Our approach incorporates the latest advancements in phantom research using tissue-mimicking material and 3D-printing with water-soluble resin to create wall-less patient-specific lumens, compatible for ultrasound and MRI. RESULTS: We successfully produced three distinct phantoms: a slanted pipe, a y-shape phantom representing a bifurcating vessel and an arteriovenous malformation (AVM) derived from clinical Digital Subtraction Angiography (DSA)-data of the brain. We present 3D ultrafast power Doppler imaging results from these phantoms, demonstrating their ability to mimic complex flow patterns as observed in the human brain. Furthermore, we showcase the compatibility of our phantom with Magnetic Resonance Imaging (MRI). CONCLUSION: We developed an MRI- and Doppler Ultrasound-compatible flow-phantom using customizable, water-soluble resin prints ranging from geometrical forms to patient-specific vasculature.

Case report: High-resolution, intra-operative µDoppler-imaging of spinal cord hemangioblastoma.

Surgical resection of spinal cord hemangioblastomas remains a challenging endeavor: the neurosurgeon's aim to reach total tumor resections directly endangers their aim to minimize post-operative neurological deficits. The currently available tools to guide the neurosurgeon's intra-operative decision-making consist mostly of pre-operative imaging techniques such as MRI or MRA, which cannot cater to intra-operative changes in field of view. For a while now, spinal cord surgeons have adopted ultrasound and its submodalities such as Doppler and CEUS as intra-operative techniques, given their many benefits such as real-time feedback, mobility and ease of use. However, for highly vascularized lesions such as hemangioblastomas, which contain up to capillary-level microvasculature, having access to higher-resolution intra-operative vascular imaging could potentially be highly beneficial. µDoppler-imaging is a new imaging modality especially fit for high-resolution hemodynamic imaging. Over the last decade, µDoppler-imaging has emerged as a high-resolution, contrast-free sonography-based technique which relies on High-Frame-Rate (HFR)-ultrasound and subsequent Doppler processing. In contrast to conventional millimeter-scale (Doppler) ultrasound, the µDoppler technique has a higher sensitivity to detect slow flow in the entire field-of-view which allows for unprecedented visualization of blood flow down to sub-millimeter resolution. In contrast to CEUS, µDoppler is able to image high-resolution details continuously, without being contrast bolus-dependent. Previously, our team has demonstrated the use of this technique in the context of functional brain mapping during awake brain tumor resections and surgical resections of cerebral arteriovenous malformations (AVM). However, the application of µDoppler-imaging in the context of the spinal cord has remained restricted to a handful of mostly pre-clinical animal studies. Here we describe the first application of µDoppler-imaging in the case of a patient with two thoracic spinal hemangioblastomas. We demonstrate how µDoppler is able to identify intra-operatively and with high-resolution, hemodynamic features of the lesion. In contrast to pre-operative MRA, µDoppler could identify intralesional vascular details, in real-time during the surgical procedure. Additionally, we show highly detailed post-resection images of physiological human spinal cord anatomy. Finally, we discuss the necessary future steps to push µDoppler to reach actual clinical maturity.

Functional imaging of the exposed brain.

When the brain is exposed, such as after a craniotomy in neurosurgical procedures, we are provided with the unique opportunity for real-time imaging of brain functionality. Real-time functional maps of the exposed brain are vital to ensuring safe and effective navigation during these neurosurgical procedures. However, current neurosurgical practice has yet to fully harness this potential as it pre-dominantly relies on inherently limited techniques such as electrical stimulation to provide functional feedback to guide surgical decision-making. A wealth of especially experimental imaging techniques show unique potential to improve intra-operative decision-making and neurosurgical safety, and as an added bonus, improve our fundamental neuroscientific understanding of human brain function. In this review we compare and contrast close to twenty candidate imaging techniques based on their underlying biological substrate, technical characteristics and ability to meet clinical constraints such as compatibility with surgical workflow. Our review gives insight into the interplay between technical parameters such sampling method, data rate and a technique's real-time imaging potential in the operating room. By the end of the review, the reader will understand why new, real-time volumetric imaging techniques such as functional Ultrasound (fUS) and functional Photoacoustic Computed Tomography (fPACT) hold great clinical potential for procedures in especially highly eloquent areas, despite the higher data rates involved. Finally, we will highlight the neuroscientific perspective on the exposed brain. While different neurosurgical procedures ask for different functional maps to navigate surgical territories, neuroscience potentially benefits from all these maps. In the surgical context we can uniquely combine healthy volunteer studies, lesion studies and even reversible lesion studies in in the same individual. Ultimately, individual cases will build a greater understanding of human brain function in general, which in turn will improve neurosurgeons' future navigational efforts.

High-resolution micro-Doppler imaging during neurosurgical resection of an arteriovenous malformation: illustrative case.

OBJECTIVE: Given the high-risk nature of arteriovenous malformation (AVM) resections, accurate pre- and intraoperative imaging of the vascular morphology is a crucial component that may contribute to successful surgical results. Surprisingly, current gold standard imaging techniques for surgical guidance of AVM resections are mostly preoperative, lacking the necessary flexibility to cater to intraoperative changes. Micro-Doppler imaging is a unique high-resolution technique relying on high frame rate ultrasound and subsequent Doppler processing of microvascular hemodynamics. In this paper the authors report the first application of intraoperative, coregistered magnetic resonance/computed tomograpy, micro-Doppler imaging during the neurosurgical resection of an AVM in the parietal lobe. OBSERVATIONS: The authors applied intraoperative two-dimensional and three-dimensional (3D) micro-Doppler imaging during resection and were able to identify key anatomical features including draining veins, supplying arteries and microvasculature in the nidus itself. Compared to the corresponding preoperative 3D-digital subtraction angiography (DSA) image, the micro-Doppler images could delineate vascular structures and visualize hemodynamics with higher, submillimeter scale detail, even at significant depths (>5 cm). Additionally, micro-Doppler imaging revealed unique microvascular morphology of surrounding healthy vasculature. LESSONS: The authors conclude that micro-Doppler imaging in its current form has clear potential as an intraoperative counterpart to preoperative contrast-dependent DSA, and the microvascular details it provides could build new ground to further study cerebrovascular pathophysiology.

Wireless closed-loop optogenetics across the entire dorsoventral spinal cord in mice.

Optoelectronic systems can exert precise control over targeted neurons and pathways throughout the brain in untethered animals, but similar technologies for the spinal cord are not well established. In the present study, we describe a system for ultrafast, wireless, closed-loop manipulation of targeted neurons and pathways across the entire dorsoventral spinal cord in untethered mice. We developed a soft stretchable carrier, integrating microscale light-emitting diodes (micro-LEDs), that conforms to the dura mater of the spinal cord. A coating of silicone-phosphor matrix over the micro-LEDs provides mechanical protection and light conversion for compatibility with a large library of opsins. A lightweight, head-mounted, wireless platform powers the micro-LEDs and performs low-latency, on-chip processing of sensed physiological signals to control photostimulation in a closed loop. We use the device to reveal the role of various neuronal subtypes, sensory pathways and supraspinal projections in the control of locomotion in healthy and spinal-cord injured mice.

How to Identify Responders and Nonresponders to Dorsal Root Ganglion-Stimulation Aimed at Eliciting Motor Responses in Chronic Spinal Cord Injury: Post Hoc Clinical and Neurophysiological Tests in a Case Series of Five Patients.

OBJECTIVE: While integrity of spinal pathways below injury is generally thought to be an important factor in the success-rate of neuromodulation strategies for spinal cord injury (SCI), it is still unclear how the integrity of these pathways conveying the effects of stimulation should be assessed. In one of our institutional case series of five patients receiving dorsal root ganglion (DRG)-stimulation for elicitation of immediate motor response in motor complete SCI, only two out of five patients presented as responders, showing immediate muscle activation upon DRG-stimulation. The current study focuses on post hoc clinical-neurophysiological tests performed within this patient series to illustrate their use for prediction of spinal pathway integrity, and presumably, responder-status. MATERIALS AND METHODS: In a series of three nonresponders and two responders (all male, American Spinal Injury Association [ASIA] impairment scale [AIS] A/B), a test-battery consisting of questionnaires, clinical measurements, as well as a series of neurophysiological measurements was performed less than eight months after participation in the initial study. RESULTS: Nonresponders presented with a complete absence of spasticity and absence of leg reflexes. Additionally, nonresponders presented with close to no compound muscle action potentials (CMAPs) or Hofmann(H)-reflexes. In contrast, both responders presented with clear spasticity, elicitable leg reflexes, CMAPs, H-reflexes, and sensory nerve action potentials, although not always consistent for all tested muscles. CONCLUSIONS: Post hoc neurophysiological measurements were limited in clearly separating responders from nonresponders. Clinically, complete absence of spasticity-related complaints in the nonresponders was a distinguishing factor between responders and nonresponders in this case series, which mimics prior reports of epidural electrical stimulation, potentially illustrating similarities in mechanisms of action between the two techniques. However, the problem remains that explicit use and report of preinclusion clinical-neurophysiological measurements is missing in SCI literature. Identifying proper ways to assess these criteria might therefore be unnecessarily difficult, especially for nonestablished neuromodulation techniques.

The Dorsal Root Ganglion as a Novel Neuromodulatory Target to Evoke Strong and Reproducible Motor Responses in Chronic Motor Complete Spinal Cord Injury: A Case Series of Five Patients.

OBJECTIVES: Current strategies for motor recovery after spinal cord injury (SCI) aim to facilitate motor performance through modulation of afferent input to the spinal cord using epidural electrical stimulation (EES). The dorsal root ganglion (DRG) itself, the first relay station of these afferent inputs, has not yet been targeted for this purpose. The current study aimed to determine whether DRG stimulation can facilitate clinically relevant motor response in motor complete SCI. MATERIALS AND METHODS: Five patients with chronic motor complete SCI were implanted with DRG leads placed bilaterally on level L4 during five days. Based on personalized stimulation protocols, we aimed to evoke dynamic (phase 1) and isotonic (phase 2) motor responses in the bilateral quadriceps muscles. On days 1 and 5, EMG-measurements (root mean square [RMS] values) and clinical muscle force measurements (MRC scoring) were used to measure motor responses and their reproducibility. RESULTS: In all patients, DRG-stimulation evoked significant phase 1 and phase 2 motor responses with an MRC ≥4 for all upper leg muscles (rectus femoris, vastus lateralis, vastus medialis, and biceps femoris) (p < 0.05 and p < 0.01, respectively), leading to a knee extension movement strong enough to facilitate assisted weight bearing. No significant differences in RMS values were observed between days 1 and 5 of the study, indicating that motor responses were reproducible. CONCLUSION: The current paper provides first evidence that bilateral L4 DRG stimulation can evoke reproducible motor responses in the upper leg, sufficient for assisted weight bearing in patients with chronic motor complete SCI. As such, a new target for SCI treatment has surfaced, using existing stimulation devices, making the technique directly clinically accessible.

Functional Ultrasound (fUS) During Awake Brain Surgery: The Clinical Potential of Intra-Operative Functional and Vascular Brain Mapping.

BACKGROUND AND PURPOSE: Oncological neurosurgery relies heavily on making continuous, intra-operative tumor-brain delineations based on image-guidance. Limitations of currently available imaging techniques call for the development of real-time image-guided resection tools, which allow for reliable functional and anatomical information in an intra-operative setting. Functional ultrasound (fUS), is a new mobile neuro-imaging tool with unprecedented spatiotemporal resolution, which allows for the detection of small changes in blood dynamics that reflect changes in metabolic activity of activated neurons through neurovascular coupling. We have applied fUS during conventional awake brain surgery to determine its clinical potential for both intra-operative functional and vascular brain mapping, with the ultimate aim of achieving maximum safe tumor resection. METHODS: During awake brain surgery, fUS was used to image tumor vasculature and task-evoked brain activation with electrocortical stimulation mapping (ESM) as a gold standard. For functional imaging, patients were presented with motor, language or visual tasks, while the probe was placed over (ESM-defined) functional brain areas. For tumor vascular imaging, tumor tissue (pre-resection) and tumor resection cavity (post-resection) were imaged by moving the hand-held probe along a continuous trajectory over the regions of interest. RESULTS: A total of 10 patients were included, with predominantly intra-parenchymal frontal and temporal lobe tumors of both low and higher histopathological grades. fUS was able to detect (ESM-defined) functional areas deep inside the brain for a range of functional tasks including language processing. Brain tissue could be imaged at a spatial and temporal resolution of 300 µm and 1.5-2.0 ms respectively, revealing real-time tumor-specific, and healthy vascular characteristics. CONCLUSION: The current study presents the potential of applying fUS during awake brain surgery. We illustrate the relevance of fUS for awake brain surgery based on its ability to capture both task-evoked functional cortical responses as well as differences in vascular characteristics between tumor and healthy tissue. As current neurosurgical practice is still pre-dominantly leaning on inherently limited pre-operative imaging techniques for tumor resection-guidance, fUS enters the scene as a promising alternative that is both anatomically and physiologically informative.