Closed-loop DBS triggered by real-time movement and tremor decoding based on thalamic LFPs for essential tremor.

High frequency Deep Brain Stimulation (DBS) targeting the motor thalamus is an effective therapy for essential tremor (ET). However, since tremor mainly affects periods of voluntary movements and sustained postures in ET, conventional continuous stimulation may deliver unnecessary current to the brain. Here we tried to decode movement states based on local field potentials (LFPs) recorded from motor thalamus and zona incerta in real-time to trigger the switching on and off of DBS in three patients with ET. Patient-specific models were first identified using thalamic LFPs recorded while the patient performed movements that tended to trigger tremor in everyday life. During the real-time test, LFPs were continuously recorded to decode movements and tremor, and the detection triggered stimulation. Results show that voluntary movements can be detected with a mean sensitivity ranging from 76.8% to 88.6% and a false positive rate ranging from 16.0% to 23.1% Postural tremor was detected with similar accuracy. The closed-loop DBS triggered by tremor detection suppressed intention tremor by 90.5% with a false positive rate of 20.3%.Clinical Relevance- This is the first study on closed-loop DBS triggered by real-time movement and tremor decoding based solely on thalamic LFPs. The results suggest that responsive DBS based on movement and tremor detection can be achieved without any requirement for external sensors or additional electrocorticography strips

Closed-Loop Deep Brain Stimulation for Essential Tremor Based on Thalamic Local Field Potentials.

BACKGROUND: High-frequency thalamic stimulation is an effective therapy for essential tremor, which mainly affects voluntary movements and/or sustained postures. However, continuous stimulation may deliver unnecessary current to the brain due to the intermittent nature of the tremor. OBJECTIVE: We proposed to close the loop of thalamic stimulation by detecting tremor-provoking movement states using local field potentials recorded from the same electrodes implanted for stimulation, so that the stimulation is only delivered when necessary. METHODS: Eight patients with essential tremor participated in this study. Patient-specific support vector machine classifiers were first trained using data recorded while the patient performed tremor-provoking movements. Then, the trained models were applied in real-time to detect these movements and triggered the delivery of stimulation. RESULTS: Using the proposed method, stimulation was switched on for 80.37 ± 7.06% of the time when tremor-evoking movements were present. In comparison, the stimulation was switched on for 12.71 ± 7.06% of the time when the patients were at rest and tremor-free. Compared with continuous stimulation, a similar amount of tremor suppression was achieved while only delivering 36.62 ± 13.49% of the energy used in continuous stimulation. CONCLUSIONS: The results suggest that responsive thalamic stimulation for essential tremor based on tremor-provoking movement detection can be achieved without any requirement for external sensors or additional electrocorticography strips. Further research is required to investigate whether the decoding model is stable across time and generalizable to the variety of activities patients may engage with in everyday life. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Highly Active Microbial Phosphoantigen Induces Rapid yet Sustained MEK/Erk- and PI-3K/Akt-Mediated Signal Transduction in Anti-Tumor Human γδ T-Cells

BACKGROUND: The unique responsiveness of Vgamma9Vdelta2 T-cells, the major gammadelta subset of human peripheral blood, to non-peptidic prenyl pyrophosphate antigens constitutes the basis of current gammadelta T-cell-based cancer immunotherapy strategies. However, the molecular mechanisms responsible for phosphoantigen-mediated activation of human gammadelta T-cells remain unclear. In particular, previous reports have described a very slow kinetics of activation of T-cell receptor (TCR)-associated signal transduction pathways by isopentenyl pyrophosphate and bromohydrin pyrophosphate, seemingly incompatible with direct binding of these antigens to the Vgamma9Vdelta2 TCR. Here we have studied the most potent natural phosphoantigen yet identified, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), produced by Eubacteria and Protozoa, and examined its gammadelta T-cell activation and anti-tumor properties. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a comparative study between HMB-PP and the anti-CD3epsilon monoclonal antibody OKT3, used as a reference inducer of bona fide TCR signaling, and followed multiple cellular and molecular gammadelta T-cell activation events. We show that HMB-PP activates MEK/Erk and PI-3K/Akt pathways as rapidly as OKT3, and induces an almost identical transcriptional profile in Vgamma9(+) T-cells. Moreover, MEK/Erk and PI-3K/Akt activities are indispensable for the cellular effects of HMB-PP, including gammadelta T-cell activation, proliferation and anti-tumor cytotoxicity, which are also abolished upon antibody blockade of the Vgamma9(+) TCR Surprisingly, HMB-PP treatment does not induce down-modulation of surface TCR levels, and thereby sustains gammadelta T-cell activation upon re-stimulation. This ultimately translates in potent human gammadelta T-cell anti-tumor function both in vitro and in vivo upon transplantation of human leukemia cells into lymphopenic mice, CONCLUSIONS/SIGNIFICANCE: The development of efficient cancer immunotherapy strategies critically depends on our capacity to maximize anti-tumor effector T-cell responses. By characterizing the intracellular mechanisms of HMB-PP-mediated activation of the highly cytotoxic Vgamma9(+) T-cell subset, our data strongly support the usage of this microbial antigen in novel cancer clinical trials

Beta-triggered adaptive deep brain stimulation during reaching movement in Parkinson's disease.

Subthalamic nucleus (STN) beta-triggered adaptive deep brain stimulation (ADBS) has been shown to provide clinical improvement comparable to conventional continuous DBS (CDBS) with less energy delivered to the brain and less stimulation induced side-effects. However, several questions remain unanswered. First, there is a normal physiological reduction of STN beta band power just prior to and during voluntary movement. ADBS systems will therefore reduce or cease stimulation during movement in people with Parkinson's disease (PD) and could therefore compromise motor performance compared to CDBS. Second, beta power was smoothed and estimated over a time period of 400 ms in most previous ADBS studies, but a shorter smoothing period could have the advantage of being more sensitive to changes in beta power which could enhance motor performance. In this study, we addressed these two questions by evaluating the effectiveness of STN beta-triggered ADBS using a standard 400 ms and a shorter 200 ms smoothing window during reaching movements. Results from 13 people with PD showed that reducing the smoothing window for quantifying beta did lead to shortened beta burst durations by increasing the number of beta bursts shorter than 200 ms and more frequent switching on/off of the stimulator but had no behavioural effects. Both ADBS and CDBS improved motor performance to an equivalent extent compared to no DBS. Secondary analysis revealed that there were independent effects of a decrease in beta power and an increase in gamma power in predicting faster movement speed, while a decrease in beta event related desynchronization (ERD) predicted quicker movement initiation. CDBS suppressed both beta and gamma more than ADBS, whereas beta ERD was reduced to a similar level during CDBS and ADBS compared with no DBS, which together explained the achieved similar performance improvement in reaching movements during CDBS and ADBS. In addition, ADBS significantly improved tremor compared with no DBS but was not as effective as CDBS. These results suggest that STN beta-triggered ADBS is effective in improving motor performance during reaching movements in people with PD, and that shortening of the smoothing window does not result in any additional behavioural benefit. When developing ADBS systems for PD, it might not be necessary to track very fast beta dynamics; combining beta, gamma, and information from motor decoding might be more beneficial with additional biomarkers needed for optimal treatment of tremor

The VANDELS ESO public spectroscopic survey: Observations and first data release

This paper describes the observations and the first data release (DR1) of the ESO public spectroscopic survey “VANDELS, a deep VIMOS survey of the CANDELS CDFS and UDS fields”. The main targets of VANDELS are star-forming galaxies at redshift 2.4 < z < 5.5, an epoch when the Universe had not yet reached 20% of its current age, and massive passive galaxies in the range 1 < z < 2.5. By adopting a strategy of ultra-long exposure times, ranging from a minimum of 20 h to a maximum of 80 h per source, VANDELS is specifically designed to be the deepest-ever spectroscopic survey of the high-redshift Universe. Exploiting the red sensitivity of the refurbished VIMOS spectrograph, the survey is obtaining ultra-deep optical spectroscopy covering the wavelength range 4800–10 000 Å with a sufficiently high signal-to-noise ratio to investigate the astrophysics of high-redshift galaxy evolution via detailed absorption line studies of well-defined samples of high-redshift galaxies. VANDELS-DR1 is the release of all medium-resolution spectroscopic data obtained during the first season of observations, on a 0.2 square degree area centered around the CANDELS-CDFS (Chandra deep-field south) and CANDELS-UDS (ultra-deep survey) areas. It includes data for all galaxies for which the total (or half of the total) scheduled integration time was completed. The DR1 contains 879 individual objects, approximately half in each of the two fields, that have a measured redshift, with the highest reliable redshifts reaching zspec ~ 6. In DR1 we include fully wavelength-calibrated and flux-calibrated 1D spectra, the associated error spectrum and sky spectrum, and the associated wavelength-calibrated 2D spectra. We also provide a catalog with the essential galaxy parameters, including spectroscopic redshifts and redshift quality flags measured by the collaboration. We present the survey layout and observations, the data reduction and redshift measurement procedure, and the general properties of the VANDELS-DR1 sample. In particular, we discuss the spectroscopic redshift distribution and the accuracy of the photometricredshifts for each individual target category, and we provide some examples of data products for the various target typesand the different quality flags. All VANDELS-DR1 data are publicly available and can be retrieved from the ESO archive. Two further data releases are foreseen in the next two years, and a final data release is currently scheduled for June 2020, which will include an improved rereduction of the entire spectroscopic data set

Adaptive deep brain stimulation for movement disorders: the long road to clinical therapy.

Continuous high-frequency DBS is an established treatment for essential tremor and Parkinson's disease. Current developments focus on trying to widen the therapeutic window of DBS. Adaptive DBS (aDBS), where stimulation is dynamically controlled by feedback from biomarkers of pathological brain circuit activity, is one such development. Relevant biomarkers may be central, such as local field potential activity, or peripheral, such as inertial tremor data. Moreover, stimulation may be directed by the amplitude or the phase (timing) of the biomarker signal. In this review, we evaluate existing aDBS studies as proof-of-principle, discuss their limitations, most of which stem from their acute nature, and propose what is needed to take aDBS into a chronic setting. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Societ

Artefact-free recording of local field potentials with simultaneous stimulation for closed-loop Deep-Brain Stimulation

Continuous high frequency Deep Brain Stimulation (DBS) is a standard therapy for several neurological disorders. Closed-loop DBS is expected to further improve treatment by providing adaptive, on-demand therapy. Local field potentials (LFPs) recorded from the stimulation electrodes are the most often used feedback signal in closed-loop DBS. However, closed-loop DBS based on LFPs requires simultaneous recording and stimulating, which remains a challenge due to persistent stimulation artefacts that distort underlying LFP biomarkers. Here we first investigate the nature of the stimulation-induced artefacts and review several techniques that have been proposed to deal with them. Then we propose a new method to synchronize the sampling clock with the stimulation pulse so that the stimulation artefacts are never sampled, while at the same time the Nyquist-Shannon theorem is satisfied for uninterrupted LFP recording. Test results show that this method achieves true uninterrupted artefact-free LFP recording over a wide frequency band and for a wide range of stimulation frequencies

Insulin-like growth factor-1 regulates the mechanosensitivity of chondrocytes by modulating TRPV4

Both mechanical and biochemical stimulation are required for maintaining the integrity of articular cartilage. However, chondrocytes respond differently to mechanical stimuli in osteoarthritic cartilage when biochemical signaling pathways, such as Insulin-like Growth Factor-1 (IGF-1), are altered. The Transient Receptor Potential Vanilloid 4 (TRPV4) channel is central to chondrocyte mechanotransduction and regulation of cartilage homeostasis. Here, we propose that changes in IGF-1 can modulate TRPV4 channel activity. We demonstrate that physiologic levels of IGF-1 suppress hypotonic-induced TRPV4 currents and intracellular calcium flux by increasing apparent cell stiffness that correlates with actin stress fiber formation. Disruption of F-actin following IGF-1 treatment results in the return of the intracellular calcium response to hypotonic swelling. Using point mutations of the TRPV4 channel at the microtubule-associated protein 7 (MAP-7) site shows that regulation of TRPV4 by actin is mediated via the interaction of actin with the MAP-7 domain of TRPV4. We further highlight that ATP release, a down-stream response to mechanical stimulation in chondrocytes, is mediated by TRPV4 during hypotonic challenge. This response is significantly abrogated with IGF-1 treatment. As chondrocyte mechanosensitivity is greatly altered during osteoarthritis progression, IGF-1 presents as a promising candidate for prevention and treatment of articular cartilage damage