Particle therapy is usually delivered using a large and costly gantry to change the angle of incidence of the therapeutic ion beam relative to the patient. If the patient were rotated instead, a simpler fixed-beam configuration could provide 360° access for the particle beam. During patient rotation, however, the changing direction of the gravitational force will deform and displace the tumour and surrounding organs in an unpredictable way. To ensure precise dose delivery to the tumour, such anatomical changes must be detected and compensated for during irradiation.

“Image guidance is absolutely necessary for particle therapy with patient rotation,” explains Kilian Dietrich from Heidelberg University Hospital and the German Cancer Research Center (DKFZ). “To exploit the main benefit of particle therapy – high dose escalation at the tumour with minimal dose to surrounding healthy tissue – prior knowledge of the tissue composition in the irradiation path is required.”

In conventional photon-based radiotherapy, MRI can be implemented in so-called MR-linacs, which offer the possibility to visualize changes in anatomy or patient position with high soft-tissue contrast. However, combining MRI with particle therapy including patient rotation remains a significant challenge.

Particle beams of protons, carbon ions or helium ions are extremely sensitive to non-homogeneous materials in the irradiation path, placing constraints on the MRI magnet and components. To address these limitations, Dietrich and colleagues are developing a radiation-transparent body coil to enable MR-guided particle therapy in combination with patient rotation, describing their work in Medical Physics.

Radiation transparency

One key obstacle when integrating MRI with particle therapy is the design of the radiofrequency (RF) coils used to flip the magnetization of the tissue and receive the generated MR signals. Conventional imaging coils contain highly attenuating electronic components that, if located in the beam path, will cause ion attenuation and scattering that alter the delivered dose distribution and reduce treatment efficacy.

To prevent such adverse effects, the team designed an RF coil with minimal ion attenuation, based on a cylindrical 16-rung birdcage configuration. This specific birdcage coil only has capacitors on the end rings, thereby avoiding attenuation and scattering in a large window in between. And since the birdcage functions both as a transmit and a receive coil, no additional RF coils are required. The design also allows easy integration into a capsule that enables rotation of the patient and the coil together, providing 360° access for a fixed ion beam source.

The researchers built the RF coil from a 35 µm-thick copper conductor embedded between layers of flexible polyimide and adhesive. The coil has an inner diameter of 53 cm and an axial length of 52 cm – providing a large enough field-of-view for full-body cross section imaging.

Measuring the Bragg peak shift caused by the entire RF coil confirmed its total water equivalent thickness (WET, a measure of ion attenuation) as 420 µm. This includes the polyimide and adhesive layers, which are homogeneous and can be compensated for with higher particle beam energy. The WET of the copper layer alone, which is inhomogeneous and cannot simply be compensated for, was approximately 210 µm. This is well within the clinical precision required for dose planning, which lies in the order of millimetres. As such, the team classifies the RF coil as radiation transparent.

Effective imaging

To characterize the imaging quality of their RF coil, the researchers imaged a homogeneous tissue-simulating phantom using a 1.5 T MR system. For the three central planes in the phantom, the transmit RF field distributions were homogeneous and resembled those of simulations and the MR system’s internal body coil. The measured transmit power efficiencies (between 0.17 and 0.26 µT/√W) were lower than the simulated values, but exceeded those of the internal body coil.

To examine the impact of coil rotation, they determined the mean transmit power efficiency in a central subvolume of the phantom for a full capsule rotation. Compared with the simulations, the measurements showed a slight dependence on rotation angle, with optimal transmit power efficiency at rotation angles close to 0° and 180°.

The RF coil also exhibited uniform signal acquisition in the three central phantom planes, with similar receive sensitivity profiles as observed in the simulations, both with the phantom in the horizontal position and when rotated by 30°. For a full rotation of the capsule, the measured receive sensitivity varied between 62% and 125%, decreasing at rotation angles between 15° and 120° and at 205°.

The signal-to-noise ratio (SNR) of the RF body coil showed a slight dependence on the rotation angle, ranging between 103 and 150. Overall, an increase of 10%–43% over the SNR of the internal body coil was achieved, indicating reasonable imaging quality for thoracic, abdominal and pelvic MRI.

To estimate the effect of realistic patient loading in the RF coil, the team also simulated a heterogeneous human voxel model, observing high transmit power efficiency and receive sensitivity for all rotation angles. The next step will be to perform in vivo measurements.

“The RF coil has not been tested in vivo yet since further tests are necessary before the whole setup can be tested,” Dietrich tells Physics World. “This includes patient acceptance for the rotation system as well as the time required to rescue the patient in times of emergency.”

The post Radiation-transparent RF coil designed for MR guidance of particle therapy appeared first on Physics World.

Cystic fibrosis is a genetic disorder in which defects in the CFTR protein (arising from mutations in the CFTR gene) can cause life-threatening symptoms in multiple organs. In the respiratory system, cystic fibrosis dehydrates the airway and produces sticky mucus in the lungs, leading to breathing problems and increasing the risk of lung infections.

One proposed treatment for cystic fibrosis is gene therapy, in which a viral vector delivers a healthy copy of the CFTR gene into airway cells to produce functional CFTR protein. To transport this vector to target cells and keep it there long enough to interact with them – key challenges for all gene therapies – researchers have coupled the vector to magnetic nanoparticles, which should allow controlled delivery to the airways using an external magnetic field.

Researchers at the University of Adelaide are now tackling another pressing challenge for successful gene therapy – visualizing the magnetic nanoparticles within live airways and manipulating them in vivo. To achieve this, they explored the use of dark-field X-ray imaging to enhance nanoparticle contrast and understand how magnetic nanoparticles move within the airway of a live rat, reporting their findings in Physics in Medicine & Biology.

While conventional X-ray imaging relies on the absorption of X-rays, dark-field X-ray imaging detects small-angle scattering from microstructures within a sample. To perform dark-field imaging, the researchers used a 25.0 keV monochromatic beam at the SPring-8 Synchrotron in Japan. They placed a phase grid into the beam upstream of the sample, creating a pattern of beamlets at the detector. These beamlets diffuse as they scatter through the sample, and the dark-field signal can be extracted from the strength of this blurring at the detector.

“My group previously used high-resolution phase-contrast X-ray imaging for imaging nanoparticle delivery, and we were at the synchrotron when we realised the images weren’t showing the full picture,” first author Ronan Smith tells Physics World. “I developed new methods for directional dark-field imaging during my PhD, so we thought we’d see if that could help.”

Imaging nanoparticle delivery

The researchers first examined the delivery of superparamagnetic nanoparticles to an anaesthetized rat, positioned with the synchrotron beam passing through its trachea at 45°. Imaging a living animal inevitably creates background signals from the surrounding anatomy. To supress this background during nanoparticle delivery, the team employed a novel approach based on analysing the components of the directional dark-field signal.

A suspension of nanoparticles should scatter X-rays isotropically, and the major and minor scattering components of the directional dark-field signal should be equal. Asymmetric structures such as tissue, skin and hair, however, will scatter anisotropically, with most of the signal seen in the major component. By examining just the minor component, the team could enhance the contrast of the nanoparticles signal above the background.

“The directional dark-field retrieval approach was key in isolating the isotropic dark-field signal, generated by nanoparticles entering the airways, from the overlying directional dark-field signal generated by the surrounding anatomy,” Smith explains. “No one has taken this approach before as far as I know.”

Smith and colleagues delivered the nanoparticles into the rat’s trachea over 25 s, capturing 180 frames during this time, guided by the animal’s breathing. Initially, a diagonal line appeared in both the X-ray transmission and dark-field images, showing the nanoparticles starting to flow from the delivery tube into the trachea. At 22.91 s, the minor dark-field signal revealed a noticeable feature in the lower half of the tube, which became gradually clearer before being pushed out by an air bubble at the end of the delivery. The dark-field signal captured this event with 3.5 times higher signal-to-noise ratio than the transmission signal.

Imaging the delivery process revealed that the nanoparticles unexpectedly settled inside the delivery tube, with many only reaching the trachea during the last 10% of the delivery. The researchers note that this could lead to suboptimal cellular uptake of viral vectors being delivered by nanoparticles, adding that this process could not have been observed without dark-field imaging.

Rotating nanoparticle strings

Next, the team exposed the rat to a 1.17 T magnet, which caused the nanoparticles to form into string-like structures, and rotated the magnet around its trachea. With the magnet above the rat, transmission images showed that the strings were aligned vertically. As the magnet moved, the strings remained aligned to the magnetic field, suggesting that dynamic magnetic fields could indeed manipulate nanoparticles in situ.

With the magnet alongside the rat (partially aligning the strings along the beam axis), the strings also produced a directional dark-field signal. However, this signal was not clearly visible when the particles were aligned vertically, likely due to the beam passing through fewer nanoparticles in this position.

Smith says that the biologists in his group are now using these imaging results to enhance their work on airway gene therapy. “It’s a cyclic development process, so we have more synchrotron experiments planned to answer the questions that their results give, using a mixture of phase-contrast and directional dark-field imaging,” he explains. “We are also looking at other respiratory applications of dark-field imaging.”

The post Dark-field X-ray imaging reveals potential of nanoparticle-delivered gene therapy appeared first on Physics World.

The oncology information system (OIS) lies at the heart of all cancer care, managing the entire clinical pathway – from patient registration, to treatment scheduling and delivery, to follow-up. The software revolution has transformed cancer care from paper-based charts and records to today’s fully digitized processes. But an OIS can do so much more: it can collect data to analyse and learn from, automate tasks and data processing, and intuitively guide users to the information that they need.

A case in point is RayCare, the OIS from oncology software specialist RaySearch Laboratories. RayCare is now used in clinics across three continents, in many cases supporting the entire chain of cancer patient management and in others, coexisting with the hospital information system or working alongside another OIS.

First launched in 2017, RayCare was built from the ground up with the users’ needs in mind. “RayCare originated as a customer need,” explains RayCare chief functionality owner Eeva-Liisa Karjalainen. “We already had our RayStation treatment planning system, which was very well received in terms of its speed and quality, and some of our customers reached out to ask why we didn’t have an OIS software as well. In parallel, we saw a need to combine the OIS and the planning software to achieve important radiotherapy goals such as efficient management of adaptive treatments.”

In response, the company set up a clinical advisory board with various hospitals and spent hundreds of hours working with nine clinics worldwide to define not just how an OIS should perform today, but what they’d like it to do in the future and how to achieve that. The aim was to not build something that already existed, but to create a system that would be useful for the future of cancer care.

At the ESTRO 2024 meeting, the company is launching RayCare 2024A, a major release that will offer a range of top-level enhancements requested by users. This includes a completely new workspace to design and manage treatment courses and scheduling from RayCare. “This brings the advantage that, together with digital workflow support and the integration with RayStation, we can make the whole treatment management process more user-friendly and more efficient,” Karjalainen explains.

And herein lies the key attribute of RayCare: its ability to increase efficiency while maintaining or improving the quality of patient care – a pressing task for cancer clinics worldwide. With an ageing population, hospitals face the challenge of providing high-quality cancer care to an increasing number of patients with a static level of resources. RayCare can help balance available resources against this increasing need for care.

Saving time through automation

RayCare’s “active workflows” provide support for the activities required throughout the entire patient pathway. Unlike prior systems, in which users had to check off finished tasks from a list and inform the next person in the workflow, RayCare actively monitors everything that happens within the system. When a task has been completed, the software automatically opens up the next task in the workflow, assigns that task to the responsible user and informs them that their next step is ready to perform.

This approach reduces lead times between activities and minimizes time spent on manual interactions. Critically, the active workflows also provide a vital safety check, by ensuring that no tasks are forgotten.

To increase efficiency further, RayCare incorporates a wide range of inherent automation features. In general, all data that should be available throughout the RaySearch systems are automatically shared and available where the user needs them, to minimize errors and the need for manual work. For instance, after a planning CT is acquired and received in RayCare, it automatically becomes available within the treatment planning system.

There’s also support for automation by use of scripting that allows users to easily configure the software to run specified actions automatically. A typical use case is to instigate generation of a treatment plan in RayStation directly from RayCare, getting it ready for a physician to review without needing any manual interaction.

“A recent example from one of our customers is the performing of scripted quality controls of a treatment plan, checking off a multitude of parameters that were previously checked manually and only pushing the plan onto an additional review if any of those checks failed,” says Karjalainen. “If the plan is within all of the quality measures, no one needs to do anything and it can go straight for approval. Otherwise it can be passed back to another staff member for review.”

Karjalainen points out that while it’s possible to use advances in radiotherapy hardware to treat more patients, for example by delivering radiation faster to reduce fraction times, the big efficiency savings will inevitably come from the automation and organizational support that software such as RayCare brings. “We see the software opportunity as a game changer,” she adds.

Patient-centred approach

Ultimately, RayCare is designed to provide a patient-centred approach based on the concept of a single oncology workflow. Patients often require more than one treatment modality in their cancer care, including surgery or medical oncology as well as radiotherapy. RayCare aims to ensure that staff in all of these disciplines can access the same patient data from one system.

“We want to bring all of these users to RayCare, to centre them around the patient and not have to transport information between different systems or institutions, which is more error prone and also shifts more responsibility to the patient,” Karjalainen explains.

The RayCare architecture already incorporates the framework to enable this type of comprehensive cancer care. And in the future, it will offer specific features such as scheduling for chemotherapy and dedicated workspaces to manage medical oncology and surgical information. This approach should enable better cross-disciplinary communication and reduce the burden on both the hospital and the patient.

“In the long term, the hope is that all activities related to oncology care would be conducted using RayCare. It will not only be the software for the radiotherapy department, but also the software for the surgery and medical oncology departments. Within one system, you could review the toxicities, the data, the outcomes and get a cohesive view on the patient’s history,” says Karjalainen. “At the same time, we are strong advocates for enabling clinics to select the best software or hardware for their clinical needs, independent of vendor. RayCare is designed to communicate with other hospital systems as one of the building blocks of the ecosystem.”

RaySearch’s commitment to supporting open interfaces and open competition is reflected in the company’s co-founding last year of the organization UniteRT, a collaboration of radiation therapy technology vendors that share the mission of complete freedom of choice for the customers.

Echoing this strong focus on supporting future technologies, RaySearch is also working on the automation of online adaptive radiotherapy, a longstanding and important clinical goal for the radiotherapy community. Online adaptive radiotherapy – in which a treatment plan is adapted to the patient’s current anatomy during the course of their treatment – requires the ability to perform extremely fast planning and replanning.

ESTRO 2024 will see the company present some of the first pieces of this project, the newly reworked fast replanning in RayStation. And in one of the next major software releases, this capability will be integrated into the RayCare software. “Truly efficient online adaptive radiotherapy is something that I’m really looking forward to becoming a reality in our RayCare clinics,” says Karjalainen.

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Complex scientific problems require large-scale resources to solve. So why not look for help from the billions of gamers around the world who spend so much time on their computers?

That’s the idea behind a new kind of citizen science, in which members of the public contribute to research projects by playing video games designed to perform specific scientific tasks.

A research team headed up at McGill University in Canada is now using this approach to understand more about the human microbiome – the tens of trillions of microbes that colonize our bodies, some of which play a vital role in our health.

Unlike most previous citizen science video games – designed for users with a specific interest in science, likely limiting their accessibility to the wider gaming community – this latest citizen science activity is integrated into a commercial video game that’s played by tens of millions of gamers.

The story began on 7 April 2020, when the team released a tile-matching mini game called Borderlands Science as a free download for the role-playing shooter–looter game Borderlands 3. Since then, as the researchers report in Nature Biotechnology, over four million players have solved more than 135 million science puzzles.

“We didn’t know whether the players of a popular game like Borderlands 3 would be interested or whether the results would be good enough to improve on what was already known about microbial evolution. But we’ve been amazed by the results,” says senior author Jérôme Waldispühl in a press statement. “In half a day, the Borderlands Science players collected five times more data about microbial DNA sequences than our earlier game, Phylo, had collected over a 10-year period.”

The mini game requires players to align rows of tiles representing the genetic building blocks of different microbes. The gamers’ efforts have helped trace the evolutionary relationships of over a million different types of bacteria in the human gut, improving upon results produced by existing computer programs. The researchers hope to use this information to understand how microbial communities are affected by diet and medications, and to relate specific types of microbes to diseases such as inflammatory bowel disease and Alzheimer’s.

“Because evolution is a great guide to function, having a better tree relating our microbes to one another gives us a more precise view of what they are doing within and around us,” explains Rob Knight from UC San Diego.

McGill’s Attila Szantner, who co-founded the Swiss IT company Massively Multiplayer Online Science (MMOS) and came up with the idea of integrating DNA analysis into a commercial video game, points out that the Borderlands Science project demonstrates the vast potential of teaming up with the gaming industry and its communities to tackle major scientific challenges.

“As almost half of the world population is playing with video games, it is of utmost importance that we find new creative ways to extract value from all this time and brainpower that we spend gaming,” Szantner says.

The post How the global gaming community is helping to solve biomedical challenges appeared first on Physics World.

The introduction of photon-counting detectors into CT scanners paved the way for the rise of spectral CT in clinical settings. Such systems employ two or more X-ray energies to create material-specific 3D maps. But since spectral CT is based on X-ray attenuation, it exhibits low contrast when imaging weakly absorbing materials such as biological tissues. As such, high-Z contrast agents are often employed to highlight structures of interest.

In parallel, X-ray phase-contrast imaging is becoming more widely available and gaining attention for both pre-clinical and clinical applications. Phase-contrast techniques, many of which can produce both attenuation and phase-shift maps, offer higher visibility of low-Z materials such as soft tissues.

“Spectral CT has proven effective in a range of applications, from material quantification to image-artefact reduction, while phase-contrast imaging boasts superior visualization of soft and microstructured tissues,” says Luca Brombal from the University of Trieste and INFN. “Building on these bases, we sought to leverage the combined strengths of both techniques.”

Brombal and colleagues, also from University College London, demonstrated the first integration of spectral and phase-contrast CT using a tomographic edge-illumination setup. The project, described in Physics in Medicine & Biology, involved developing an imaging setup that can acquire data with both spectral and phase-contrast properties, alongside the implementation of a material decomposition model.

“The benefits of the combined spectral phase-contrast approach are the possibility to simultaneously produce three mass density maps of specific elements or compounds in the sample, while improving the signal-to-noise ratio, especially of the soft-tissue component, due to phase sensitivity,” Brombal explains.

Material decomposition

The team used an edge-illumination phase-contrast set-up, in which masks placed either side of the sample shape the incident X-ray beam and selectively block the detector. A reference illumination curve is created with no sample in place. Once the sample is inserted, this curve is attenuated and laterally displaced, changes that are then used to retrieve attenuation images and calculate the sample-induced phase shift.

For this study, the researchers employed synchrotron radiation from the Italian synchrotron facility Elettra. They note, however, that translation to a laboratory setup using conventional X-ray tubes should be straightforward. They first scanned a test phantom comprising plastic cuvettes filled with five liquids: calcium chloride solution (370 and 180 mg/ml); iodine solution (50 and 10 mg/ml, similar to concentrations used in iodine-based contrasts); and distilled water.

The imaging system is based on a photon-counting detector with a small-pixel (62 µm) cadmium telluride sensor, operated in two-colour mode to record incoming photons in low- and high-energy bins. The researchers acquired tomographic images of the phantom, recording 360 projections over 180°, with an exposure time of 1.2 s per step and a total acquisition time of 2.9 h.

After reconstructing 3D volumes from the attenuation and phase projections, the team performed material decomposition using three algorithms: spectral decomposition, using the low- and high-energy attenuation reconstructions as inputs; attenuation/phase decomposition, applied to phase and attenuation reconstructions obtained by summing the energy bins; and spectral/phase decomposition, which uses low-energy, high-energy and phase reconstructions.

The spectral/phase decomposition algorithm exhibited the best performance of the three, correctly identifying all materials with no signal contamination across channels and significantly less noise than standard spectral decomposition, due to the low noise of the input phase channel. This algorithm computed values closest to the nominal mass density, with RMS errors of 1.1%, 1.9% and 3.5% for water, iodine and calcium chloride solutions, respectively.

Spectral/phase decomposition also improved the signal-to-noise ratio of the images, by a factor of nine in the water channel and a factor of 1.3 in iodine images, compared with spectral decomposition. In addition, only the spectral/phase decomposition enabled simultaneous quantification of all three material densities.

Biological demonstration

To validate the technique using a biological sample, the researchers imaged ex vivo a laboratory mouse perfused post-mortem with an iodine-based vascular contrast agent. They acquired 720 projections over 360°, with a total exposure time of 5.8 h and a resulting radiation dose of around 2 Gy. They note that for future in vivo applications the delivered dose could be reduced to hundreds of milligray, by optimizing the mask design, for example, or using more dose-efficient acquisition schemes.

To preserve high-resolution details, the researchers reconstructed attenuation and phase images with a 20 µm³ voxel size. Spectral attenuation images showed signal from bones (calcium map) and vasculature (iodine map), but no soft-tissue signal. The phase input reconstruction, meanwhile, revealed soft-tissue structures such as cutaneous and subcutaneous layers and internal organs

Material decomposition using the spectral/phase algorithm clearly separated the vasculature and bones, with no contamination signal, while the phase channel provided good visibility of the formalin-fixed soft-tissue component.

The high resolution of the iodine and calcium images demonstrated that the system can capture blood vessels smaller than 50 µm, as well as the fine trabecular structure of the bone. The researchers also created a 3D rendering of the mouse sample reconstruction after spectral/phase decomposition, which simultaneously visualizes soft tissues, bones and vasculature.

The next step, Brombal tells Physics World, will be to translate this technique from a proof-of-principle study to more compelling scientific cases. “We recently started a new project focused on the application of spectral phase-contrast to osteoarticular research, especially in the context of detection of diseases such as osteoarthritis, and to (quantitative) virtual histology, potentially providing complementary insights alongside conventional pathological analysis of surgical tissue specimens.”

The post Spectral and phase-contrast CT combine strengths to enhance X-ray imaging appeared first on Physics World.

Damage to the spinal cord, whether by injury or disease, can have devastating impacts on health, including loss of motor or sensory functions, or chronic back pain, which affects an estimated 540 million people at any given time. A US-based research team has now used functional ultrasound imaging (fUSI) to visualize the spinal cord and map its response to electrical stimulation in real time, an approach that could improve treatments of chronic back pain.

Despite playing a central role in sensory, motor and autonomic functions, little is known about the functional architecture of the human spinal cord. Traditional neuroimaging techniques, such as functional MRI (fMRI), are impeded by strong motion artefacts generated by heart pulsation and breathing.

In contrast, fUSI is less impacted by motion artefacts and can image the spinal cord with high spatiotemporal resolution (roughly 100 µm and up to 100 ms) and high sensitivity to slow flowing blood during surgery. It works by emitting ultrasonic waves into an area-of-interest and detecting the echoed signal from blood cells flowing in that region (the power Doppler signal). Another advantage is that the fUSI scanner is mobile, eliminating the extensive infrastructure required for fMRI systems.

“The spinal cord houses the neural circuitry that controls and modulates some of the most important functions of life, such as breathing, swallowing and micturition. However, it has been frequently neglected in the study of neural function,” explains lead contact Vasileios Christopoulos from the University of California Riverside. “Functional ultrasound imaging overcomes the limitations of traditional neuroimaging technologies and can monitor the activity of the spinal cord with higher spatiotemporal resolution and sensitivity than fMRI.”

Previous research demonstrated that fUSI can measure brain activity in animals and human patients, including one study showing that low-frequency fluctuations in the power Doppler signal are strongly correlated with neuronal activity. More recently, researchers used fUSI to image spinal cord responses to electrical stimulation in animals.

In this latest work, Christopoulos and colleagues – also from the USC Neurorestoration Center at the Keck School of Medicine – used fUSI to characterize haemodynamic activity (changes in blood flow) in the spinal cord in response to epidural electrical spinal cord stimulation (ESCS) – a neuromodulation tool employed to treat pain conditions that don’t respond to traditional therapies.

In a first in-human study, the team monitored haemodynamic activity in six patients undergoing implantation of a therapeutic ESCS device to treat chronic back pain, reporting the findings in Neuron.

Utilizing a similar mechanism to fMRI, fUSI relies on the neurovascular coupling phenomenon, in which increased neural activity causes localized changes in blood flow to meet the metabolic demands of active neurons. The team used a miniaturized 15-MHz linear array transducer to perform fUSI, inserting it surgically onto the spinal cord at the tenth thoracic vertebra (T10), with the stimulation electrodes placed to span the T8–9 spinal segments. The recorded images had a 100 x 100 µm spatial resolution, a slice thickness of about 400 µm and a 12.8 x 10 mm field-of-view.

Four patients received 10 ON–OFF cycles of low-current (3.0 mA) stimulation, comprising 30 s with stimulation then 30 s without. Stimulation caused regional changes in spinal cord haemodynamics, with some regions exhibiting significant increases in blood flow and others showing significant decreases. Once the stimulation was switched off, blood flow returned to the initial condition.

To assess whether fUSI can detect haemodynamic changes associated with different stimulation protocols, the remaining two patients received five ON–OFF cycles of 3.0 mA stimulation followed by five cycles of 4.5 mA stimulation, with a 3-min pause between the two. The researchers found that increasing the current amplitude from 3.0 to 4.5 mA did not change the spatial distribution of the activated spinal cord regions. However, high-current stimulation induced stronger haemodynamic changes on the spinal cord.

This ability of fUSI to differentiate haemodynamic responses evoked by different ESCS currents is an important step towards developing an ultrasound-based clinical monitoring system to optimize stimulation parameters. Christopoulos explains that because patients are anaesthetized during spinal cord surgery, they cannot report whether the applied electrical stimulation protocol actually reduces pain. As such, the neurosurgeon cannot accurately assess the effects of neuromodulation in real-time.

“Our study provides a first proof-of-concept that fUSI technology can be used to develop closed-loop clinical neuromodulation systems, allowing neurosurgeons to adjust stimulation parameters (pulse width, pulse shape, frequency, current amplitude, location of stimulation, etc) during surgery,” he tells Physics World.

In future, the team hopes to establish fUSI as a platform for investigating spinal cord function and developing real-time closed-loop clinical neuromodulation systems. “We recently submitted for publication a clinical study demonstrating that fUSI is capable of detecting networks in the human spinal cord where activity is strongly correlated with bladder pressure,” says Christopoulos. “This finding opens new avenues for the development of spinal cord machine interface technologies to restore bladder control in patients with urinary incontinence, such as those with spinal cord injury.”

The post Functional ultrasound imaging provides real-time feedback during spinal surgery appeared first on Physics World.

The brain’s frontal circuits play a vital role in controlling motor, cognitive and behavioural functions. Disruption of the fronto-subcortical circuits, which connect the frontal cortex in the forebrain with basal ganglia located deeper within, can result in a range of neurological disorders. It’s not clear, however, which connections are associated with which dysfunctions. To shed light on this problem and help identify potential treatment targets, an international research team has used deep brain stimulation (DBS) to map the circuits associated with four different brain disorders.

DBS is an invasive therapy in which surgically implanted electrodes modulate brain networks by electrical stimulation of target regions. One such target – the subthalamic nucleus – is of particular interest as it receives input from the entire frontal cortex to the basal ganglia. Indeed, electrical stimulation of the subthalamic nucleus has been shown to alleviate symptoms of several brain disorders.

The research team – led by Andreas Horn from the Center for Brain Circuit Therapeutics at Harvard Medical School and Charité – Universitätsmedizin Berlin, and Ningfei Li from Charité – studied a total of 534 DBS electrodes implanted to treat four brain disorders: Parkinson’s disease (PD), dystonia, obsessive-compulsive disorder (OCD) and Tourette’s syndrome (TS).

First author Barbara Hollunder and colleagues first examined data from 197 patients who had DBS electrodes bilaterally implanted in the subthalamic nucleus to treat these disorders, including 70 with dystonia, 94 with PD, 19 with OCD and 14 with TS.

For each disorder, they mapped stimulation effects at the subthalamic level across the cohort to identify the sites associated with the most beneficial stimulation. These DBS “sweet spots” differed in location on the subthalamic nucleus for the four disorders.

Next, the researchers mapped stimulation effects to the fronto-subcortical circuits, enabling them to identify which brain circuits had become dysfunctional (and could be targeted for treatment) in each disorder. The circuits that benefitted most from stimulation (referred to as “sweet streamlines”) included projections from sensorimotor cortices for dystonia, the primary motor cortex for TS, the supplementary motor area for PD, and the ventromedial prefrontal and anterior cingulate cortices for OCD.

“We were able to use brain stimulation to precisely identify and target circuits for the optimal treatment of four different disorders,” says Horn in a press statement. “In simplified terms, when brain circuits become dysfunctional, they may act as brakes for the specific brain functions that the circuit usually carries out. Applying DBS may release the brake and may in part restore functionality.”

Clinical potential

These disease-specific streamline models hold potential for guiding future clinical treatments. To confirm this capability, the researchers performed further experiments using independent data. They validated the PD and OCD streamline models (selected due to patient availability) in two additional retrospective groups of 32 and 35 patients, respectively.

In these additional patients, the researchers used the level of overlap between stimulation volumes and the respective streamline model to estimate clinical outcomes. For both disorders, they observed a good match between the estimates and improvements in symptoms.

The researchers also performed three prospective experiments using the identified circuits to improve treatment benefit. For two patients, they reprogrammed their DBS implants to maximize the overlap of stimulation volumes with the respective streamline model. The first patient, a 67-year-old male with PD, had benefited from a 60% reduction in symptoms upon conventional clinical treatment with DBS. Optimized stimulation based on streamline-guided parameters improved this treatment benefit further to a 71% reduction in symptoms.

In the second case, a 21-year-old female with severe treatment-resistant OCD, one month after streamline-based DBS reprogramming she experienced a 37% reduction in global obsessive-compulsive symptoms, compared with a 17% symptom reduction under clinical stimulation parameters.

Finally, the team implanted a pair of subthalamic electrodes to treat a 32-year-old male who had suffered from treatment-resistant OCD since the age of 18. Four weeks after surgery, with DBS informed by the streamline models, he reported a 77% reduction in global obsessive-compulsive symptoms, with improvements seen within one day of switching on the DBS.

The researchers suggest that their successful validations of the OCD and PD streamline targets may provide initial evidence for clinical applications in the context of prospective validation studies. They note that – if further confirmed – the identified circuits may represent therapeutic targets that could also be used for stereotactic targeting in neurosurgery and potentially non-invasive transcranial magnetic stimulation.

Li tells Physics World that in future, the researchers “plan to refine the model, focusing more on fine-grained dysfunctional brain circuits, and validate our findings through prospective clinical trials”.

The researchers describe their findings in Nature Neuroscience.

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