Walking naturally after spinal cord injury using a brain-spine interface.

A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain-spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4-6. A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.

A systematic review of the effects of transcranial photobiomodulation on brain activity in humans.

In recent years, transcranial photobiomodulation (tPBM) has been developing as a promising method to protect and repair brain tissues against damages. The aim of our systematic review is to examine the results available in the literature concerning the efficacy of tPBM in changing brain activity in humans, either in healthy individuals, or in patients with neurological diseases. Four databases were screened for references containing terms encompassing photobiomodulation, brain activity, brain imaging, and human. We also analysed the quality of the included studies using validated tools. Results in healthy subjects showed that even after a single session, tPBM can be effective in influencing brain activity. In particular, the different transcranial approaches - using a focal stimulation or helmet for global brain stimulation - seemed to act at both the vascular level by increasing regional cerebral blood flow (rCBF) and at the neural level by changing the activity of the neurons. In addition, studies also showed that even a focal stimulation was sufficient to induce a global change in functional connectivity across brain networks. Results in patients with neurological disease were sparser; nevertheless, they indicated that tPBM could improve rCBF and functional connectivity in several regions. Our systematic review also highlighted the heterogeneity in the methods and results generated, together with the need for more randomised controlled trials in patients with neurological diseases. In summary, tPBM could be a promising method to act on brain function, but more consistency is needed in order appreciate fully the underlying mechanisms and the precise outcomes.

In vivo quantification of magnetically labelled cells by MRI relaxometry.

Cellular MRI, which visualizes magnetically labelled cells (cells*), is an active research field for in vivo cell therapy and tracking. The simultaneous relaxation rate measurements (R2 *, R2 , R1 ) are the basis of a quantitative cellular MRI method proposed here. U937 cells were labelled with Molday ION Rhodamine B, a bi-functional superparamagnetic and fluorescent nanoparticle (U937*). U937* viability and proliferation were not affected in vitro. In vitro relaxometry was performed in a cell concentration range of [2.5 × 104 -108 ] cells/mL. These measurements show the existence of complementary cell concentration intervals where these rates vary linearly. The juxtaposition of these intervals delineates a wide cell concentration range over which one of the relaxation rates in a voxel of an in vivo image can be converted into an absolute cell concentration. The linear regime was found at high concentrations for R1 in the range of [106 - 2 × 108 ] cells/mL, at intermediate concentrations for R2 in [2.5 × 105 - 5 × 107 ] cells/mL and at low concentrations for R2 * in [8 × 104 - 5 × 106 ] cells/mL. In vivo relaxometry was performed in a longitudinal study, with labelled U937 cells injected into a U87 glioma mouse model. Using in vitro data, maps of in vivo U937* concentrations were obtained by converting one of the in vivo relaxation rates to cell concentration maps. MRI results were compared with the corresponding optical images of the same brains, showing the usefulness of our method to accurately follow therapeutic cell biodistribution in a longitudinal study. Results also demonstrate that the method quantifies a large range of magnetically labelled cells*. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of a higher dose of near-infrared light on clinical signs and neuroprotection in a monkey model of Parkinson's disease.

We have reported previously that intracranial application of near-infrared light (NIr) - when delivered at the lower doses of 25J and 35J - reduces clinical signs and offers neuroprotection in a subacute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of Parkinson's disease. In this study, we explored whether a higher NIr dose (125J) generated beneficial effects in the same MPTP monkey model (n=15). We implanted an NIr (670nm) optical fibre device within a midline region of the midbrain in macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.8-2.1mg/kg) were made over a five day period, during which time the NIr device was turned on and left on continuously throughout the ensuing three week survival period. Monkeys were evaluated clinically and their brains processed for immunohistochemistry and stereology. Our results showed that the higher NIr dose did not have any toxic impact on cells at the midbrain implant site. Further, this NIr dose resulted in a higher number of nigral tyrosine hydroxylase immunoreactive cells when compared to the MPTP group. However, the higher NIr dose monkeys showed little evidence for an increase in mean clinical score, number of nigral Nissl-stained cells and density of striatal tyrosine hydroxylase terminations. In summary, the higher NIr dose of 125J was not as beneficial to MPTP-treated monkeys as compared to the lower doses of 25J and 35J, boding well for strategies of NIr dose delivery and device energy consumption in a future clinical trial.

Near-infrared light is neuroprotective in a monkey model of Parkinson disease.

OBJECTIVE: To examine whether near-infrared light (NIr) treatment reduces clinical signs and/or offers neuroprotection in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson disease. METHODS: We implanted an optical fiber device that delivered NIr (670 nm) to the midbrain of macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.5-2.1mg/kg) were made over a 5- to 7-day period, during which time the NIr device was turned on. This was then followed by a 3-week survival period. Monkeys were evaluated clinically (eg, posture, bradykinesia) and behaviorally (open field test), and their brains were processed for immunohistochemistry and stereology. RESULTS: All monkeys in the MPTP group developed severe clinical and behavioral impairment (mean clinical scores = 21-34; n = 11). By contrast, the MPTP-NIr group developed much less clinical and behavioral impairment (n = 9); some monkeys developed moderate clinical signs (mean scores = 11-15; n = 3), whereas the majority--quite remarkably--developed few clinical signs (mean scores = 1-6; n = 6). The monkeys that developed moderate clinical signs had hematic fluid in their optical fibers at postmortem, presumably limiting NIr exposure and overall clinical improvement. NIr was not toxic to brain tissue and offered neuroprotection to dopaminergic cells and their terminations against MPTP insult, particularly in animals that developed few clinical signs. INTERPRETATION: Our findings indicate NIr to be an effective therapeutic agent in a primate model of the disease and create the template for translation into clinical trials.

In vitro demonstration of focused ultrasound thrombolysis using bifrequency excitation.

Focused ultrasound involving inertial cavitation has been shown to be an efficient method to induce thrombolysis without any pharmacological agent. However, further investigation of the mechanisms involved and further optimization of the process are still required. The present work aims at studying the relevance of a bifrequency excitation compared to a classical monofrequency excitation to achieve thrombolysis without any pharmacological agent. In vitro human blood clots were placed at the focus of a piezoelectric transducer. Efficiency of the thrombolysis was assessed by weighing each clot before and after sonication. The efficiencies of mono- (550 kHz) and bifrequency (535 and 565 kHz) excitations were compared for peak power ranging from 70 W to 220 W. The thrombolysis efficiency appears to be correlated to the inertial cavitation activity quantified by passive acoustic listening. In the conditions of the experiment, the power needed to achieve 80% of thrombolysis with a monofrequency excitation is reduced by the half with a bifrequency excitation. The thermal effects of bifrequency and monofrequency excitations, studied using MR thermometry measurements in turkey muscle samples where no cavitation occurred, did not show any difference between both types of excitations when using the same power level.

Experimental methods for improved spatial control of thermal lesions in magnetic resonance-guided focused ultrasound ablation.

Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU, or MRgFUS) is a hybrid technology that was developed to provide efficient and tolerable thermal ablation of targeted tumors or other pathologic tissues, while preserving the normal surrounding structures. Fast 3-D ablation strategies are feasible with the newly available phased-array HIFU transducers. However, unlike fixed heating sources for interstitial ablation (radiofrequency electrode, microwave applicator, infra-red laser applicator), HIFU uses propagating waves. Therefore, the main challenge is to avoid thermo-acoustical adverse effects, such as energy deposition at reflecting interfaces and thermal drift of the focal lesion toward the near field. We report here our investigations on some novel experimental solutions to solve, or at least to alleviate, these generally known tolerability problems in HIFU-based therapy. Online multiplanar MR thermometry was the main investigational tool extensively used in this study to identify the problems and to assess the efficacy of the tested solutions. We present an improved method to cancel the beam reflection at the exit window (i.e., tissue-to-air interface) by creating a multilayer protection, to dissipate the residual HIFU beam by bulk scattering. This study evaluates selective de-activation of transducer elements to reduce the collateral heating at bone surfaces in the far field, mainly during automatically controlled volumetric ablation. We also explore, using hybrid US/MR simultaneous imaging, the feasibility of using disruptive boiling at the focus, both as a far-field self-shielding technique and as an enhanced ablation strategy (i.e., boiling core controlled HIFU ablation).

Reference-free PRFS MR-thermometry using near-harmonic 2-D reconstruction of the background phase.

Proton resonance frequency shift (PRFS) MR thermometry (MRT) is the generally preferred method for monitoring thermal ablation, typically implemented with gradient-echo (GRE) sequences. Standard PRFS MRT is based on the subtraction of a temporal reference phase map and is, therefore, intrinsically sensitive to tissue motion (including deformation) and to external perturbation of the magnetic field. Reference-free (or reference-less) PRFS MRT has been previously described by Rieke and was based on a 2-D polynomial fit performed on phase data from outside the heated region, to estimate the background phase inside the region of interest. While their approach was undeniably a fundamental progress in terms of robustness against tissue motion and magnetic perturbations, the underlying mathematical formalism requires a thick unheated border and may be subject to numerical instabilities with high order polynomials. A novel method of reference-free PRFS MRT is described here, using a physically consistent formalism, which exploits mathematical properties of the magnetic field in a homogeneous or near-homogeneous medium. The present implementation requires as input the MR GRE phase values along a thin, nearly-closed and unheated border. This is a 2-D restriction of a classic Dirichlet problem, working on a slice per slice basis. The method has been validated experimentally by comparison with the "ground truth" data, considered to be the standard PRFS method for static ex vivo tissue. "Zero measurement" of the gradient-echo phase baseline was performed in healthy volunteer liver with rapid acquisition (300 ms/image). In vivo data acquired in sheep liver during MR-guided high intensity focused ultrasound (MRgHIFU) sonication were post-processed as proof of applicability in a therapeutic scenario. Bland and Altman mean absolute difference between the novel method and the "ground truth" thermometry in ex vivo static tissue ranged between 0.069 °C and 0.968 °C, compared to the inherent "white" noise SD of 0.23 °C. The accuracy and precision of the novel method in volunteer liver were found to be on average 0.13 °C and respectively 0.65 °C while the inherent "white" noise SD was on average 0.51 °C. The method was successfully applied to large ROIs, up to 6.2 cm inner diameter, and the computing time per slice was systematically less than 100 ms using C++. The current limitations of reference-free PRFS thermometry originate mainly from the need to provide a nearly-closed border, where the MR phase is artifact-free and the tissue is unheated, plus the potential need to reposition that border during breathing to track the motion of the anatomic zone being monitored.A reference-free PRFS thermometry method based on the theoretical framework of harmonic functions is described and evaluated here. The computing time is compatible with online monitoring during local thermotherapy. The current reference-free MRT approach expands the workflow flexibility, eliminates the need for respiratory triggers, enables higher temporal resolution, and is insensitive to unique-event motion of tissue.

An MR-compliant phased-array HIFU transducer with augmented steering range, dedicated to abdominal thermotherapy.

A novel architecture for a phased-array high intensity focused ultrasound (HIFU) device was investigated, aiming to increase the capabilities of electronic steering without reducing the size of the elementary emitters. The principal medical application expected to benefit from these developments is the time-effective sonication of large tumours in moving organs. The underlying principle consists of dividing the full array of transducers into multiple sub-arrays of different resonance frequencies, with the reorientation of these individual emitters, such that each sub-array can focus within a given spatial zone. To enable magnetic resonance (MR) compatibility of the device and the number of output channels from the RF generator to be halved, a passive spectral multiplexing technique was used, consisting of parallel wiring of frequency-shifted paired piezoceramic emitters with intrinsic narrow-band response. Two families of 64 emitters (circular, 5 mm diameter) were mounted, with optimum efficiency at 0.96 and 1.03 MHz, respectively. Two different prototypes of the HIFU device were built and tested, each incorporating the same two families of emitters, but differing in the shape of the rapid prototyping plastic support that accommodated the transducers (spherical cap with radius of curvature/aperture of 130 mm/150 mm and, respectively, 80 mm/110 mm). Acoustic measurements, MR-acoustic radiation force imaging (ex vivo) and MR-thermometry (ex vivo and in vivo) were used for the characterization of the prototypes. Experimental results demonstrated an augmentation of the steering range by 80% along one preferentially chosen axis, compared to a classic spherical array of the same total number of elements. The electric power density provided to the piezoceramic transducers exceeded 50 W cm(-2) CW, without circulation of coolant water. Another important advantage of the current approach is the versatility of reshaping the array at low cost.

Endocavitary thermal therapy by MRI-guided phased-array contact ultrasound: experimental and numerical studies on the multi-input single-output PID temperature controller's convergence and stability.

PURPOSE: Endocavitary high intensity contact ultrasound (HICU) may offer interesting therapeutic potential for fighting localized cancer in esophageal or rectal wall. On-line MR guidance of the thermotherapy permits both excellent targeting of the pathological volume and accurate preoperatory monitoring of the temperature elevation. In this article, the authors address the issue of the automatic temperature control for endocavitary phased-array HICU and propose a tailor-made thermal model for this specific application. The convergence and stability of the feedback loop were investigated against tuning errors in the controller's parameters and against input noise, through ex vivo experimental studies and through numerical simulations in which nonlinear response of tissue was considered as expected in vivo. METHODS: An MR-compatible, 64-element, cooled-tip, endorectal cylindrical phased-array applicator of contact ultrasound was integrated with fast MR thermometry to provide automatic feedback control of the temperature evolution. An appropriate phase law was applied per set of eight adjacent transducers to generate a quasiplanar wave, or a slightly convergent one (over the circular dimension). A 2D physical model, compatible with on-line numerical implementation, took into account (1) the ultrasound-mediated energy deposition, (2) the heat diffusion in tissue, and (3) the heat sink effect in the tissue adjacent to the tip-cooling balloon. This linear model was coupled to a PID compensation algorithm to obtain a multi-input single-output static-tuning temperature controller. Either the temperature at one static point in space (situated on the symmetry axis of the beam) or the maximum temperature in a user-defined ROI was tracked according to a predefined target curve. The convergence domain in the space of controller's parameters was experimentally explored ex vivo. The behavior of the static-tuning PID controller was numerically simulated based on a discrete-time iterative solution of the bioheat transfer equation in 3D and considering temperature-dependent ultrasound absorption and blood perfusion. RESULTS: The intrinsic accuracy of the implemented controller was approximately 1% in ex vivo trials when providing correct estimates for energy deposition and heat diffusivity. Moreover, the feedback loop demonstrated excellent convergence and stability over a wide range of the controller's parameters, deliberately set to erroneous values. In the extreme case of strong underestimation of the ultrasound energy deposition in tissue, the temperature tracking curve alone, at the initial stage of the MR-controlled HICU treatment, was not a sufficient indicator for a globally stable behavior of the feedback loop. Our simulations predicted that the controller would be able to compensate for tissue perfusion and for temperature-dependent ultrasound absorption, although these effects were not included in the controller's equation. The explicit pattern of acoustic field was not required as input information for the controller, avoiding time-consuming numerical operations. CONCLUSIONS: The study demonstrated the potential advantages of PID-based automatic temperature control adapted to phased-array MR-guided HICU therapy. Further studies will address the integration of this ultrasound device with a miniature RF coil for high resolution MRI and, subsequently, the experimental behavior of the controller in vivo.