High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.
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The research was supported by US Defense Advanced Research Projects Agency (DARPA) Microsystems Technology Office contract N66001-12-1-4045; Office of Naval Research (ONR) Global N62909-14-1-N020; National Health and Medical Research Council of Australia (NHMRC) Project Grant APP1062532 and Development Grant APP1075117; Defence Health Foundation, Australia (Booster Grant); Defence Science Institute, Australia, grant; Brain Foundation, Australia, research gift; and the Victorian Government's Operational Infrastructure Support Program. T.J.O. acknowledges the support of the Royal Melbourne Hospital Neuroscience Foundation for the Warren Haynes Fellowship, as well as the Faculty of Medicine, University of Melbourne for the Leslie Eric Paddle Scholarship in Neurology. We thank Covidien (Medtronic) for provision of 30 Solitaire stentriever devices as a product research grant, K. Wilson and S. Cudennec for MRI data acquisition; C. Hall, A. Stevenson and A. Maksimenko for synchrotron acquisition; G. Sharma and S. Salinas for imaging analysis; H. Lau and T. Vale for surgical assistance; and L. Warne for anesthetic assistance. We acknowledge the facilities, and the scientific and technical assistance of the Australian National Imaging Facility at the Melbourne Brain Centre Imaging Unit, as well as the Imaging and Medical beamline at the Australian Synchrotron, Victoria, Australia.
T.J.O. and N.L.O. hold stock in SmartStent. Patent application US20140288667A1 filed by T.J.O. applies to the method described in the paper.
Integrated supplementary information
a, Superficial venous structures were identified and reconstructed using post-contrast brain MRI images (n=50). Scale bar, 3 cm. b-c, Vein diameters were manually measured using multi-planar image reconstructions at each 5 mm fiducial point along the course of the vein. Scale bar, 5 mm. d, Pial surfaces were reconstructed and segmented for primary motor (red, Brodmann Area, BA4) and sensory (yellow, BA1) areas. Scale bar, 3 cm. e-f, The shortest distance from each venous fiducial point to the pial surface of BA4 and BA1 was measured using multi-planar reconstructions. Scale bar, 3 mm. g, 3-dimensional reconstructed venous structures and motor and sensory surfaces were superimposed to position within sulci. Scale bar, 10 mm. h, Coronal view demonstrating superior sagittal sinus. Circle of best fit within triangular measurement was recorded as diameter at each fiducial point. Scale bar, 10 mm.
a, Post-central sulcal vein (PostCSV, dotted line) reconstructed in relation to sensory cortex (yellow, Brodmann Area 1, BA1), with representative tributary feeding angle into superior sagittal sinus (SSS, dashed line). Scale bar, 2 cm. b, PostCSV lumen diameters at 5 mm increments, commencing proximally at SSS (median, IQR, range, n = 41). c, PostCSV distances to BA1 at 5 mm increments (median, IQR, range, n = 41). d, Central sulcal vein (CSV) route in relation to motor (red, BA4) and sensory (yellow, BA1) cortex. Scale bar, 2 cm. e, Angles of all veins entering SSS. PostCSV (mean 66.3° [95%CI 57.1 - 75.4], n = 30); CSV (mean 78.7° [95%CI 73.7 - 83.8], n = 49); PreCSV (mean 83.7° [95%CI 75.1 - 92.4], n = 25). f-h, Pre-central sulcal vein (PreCSV) diameters and distances in relation to motor cortex (red, BA4)(median, IQR, range). Scale bar, 2 cm.
a, Overall inter-observer reliability between two observers for superficial cortical vein diameter measurements were in almost perfect agreement (ICC = 0.84; Lin’s CCC = 0.84 [95%CI 0.82 - 0.87]; reduced major axis slope = 0.97, intercept = 0.02). b, Proximal vein diameters demonstrated moderate-to-substantial agreement (ICC = 0.63; Lin’s CCC = 0.63 [95%CI 0.53 - 0.75]; reduced major axis slope = 1.09, intercept = -0.63) with identifiable proportional bias. c, Overall intra-observer repeat diameter measurements were also in almost perfect agreement (ICC = 0.89; Lin’s CCC = 0.89 [95%CI 0.88 - 0.9]; reduced major axis slope = 1.04, intercept = -0.11). d, Proximal vein region intra-observer diameters also demonstrated mildly lower values of agreement (ICC = 0.7; Lin’s CCC = 0.7 [95%CI 0.64 - 0.76]; reduced major axis slope = 1.1, intercept = -0.3), indicative of substantial agreement.
a, Ovine vasculature mechanical model of major stress points along venous pathway indicating the jugular foramen (b) and the confluence of sinuses (c), scale bar, 1 cm. b, Internal catheter frictional force measured as stentrodes were deployed through catheters with varying internal diameters. Electrode detachment occurred only with attempts via 0.89 mm catheter (n = 3; all other catheter trials n = 9). c, Repeated measures (n = 3) compression test indicating superelasticity of stent is maintained with wire wrapping and attached electrodes. Average compression force comparison between d, long stentrodes with seven (n = 4) and eight (n = 4) electrodes, e, short stentrodes with six (n = 3) and seven (n = 4) electrodes and f, short and long stentrodes with seven electrodes each (n = 4).
a, Coaxial system including 6F sheath, 6F, 4F, 2F and microwire, all preloaded into one another. Commencing with microwire, entire system is telescoped over itself to negotiate the venous pathway toward the superior sagittal sinus (SSS). Scale bar, 5 mm. b, Plain x-ray demonstrating microwire (blue arrow) with a J shape to assist with negotiation of complex venous channels and bifurcations. 2F catheter (yellow arrow) is advanced over microwire to support entry into the SSS. Scale bar, 1 cm. c, Lateral projection digital subtraction angiography of SSS following access with 4F and prior to stentrode deployment. Scale bar, 1 cm.
Supplementary Figure 6 Identification of viable stent-mounted electrodes using electrochemical impedance spectroscopy
a, Impedance magnitude and b, phase angle of stentrode electrodes (blue) and bare metal stent (grey) immersed in saline [mean ± SD]. Dashed lines represent peak-resistance-frequency and access resistances for the stentrode electrodes (blue, 200 kHz and 816 ± 15 Ω [mean ± SD], n = 39 electrodes) and bare stent (grey, 16 kHz and 625 ± 27 Ω, n = 12 stents) immersed in saline. In saline, 10 kHz measurements are comparable with peak-resistance-frequency measured access resistance. c, Bar graph showing 10 kHz impedance of stentrode electrodes in saline (blue, 979 ± 20 Ω [mean ± SD], n = 39 electrodes), bare metal stents in saline (grey, 625 ± 27 Ω, n = 12 stents), stentrode in vivo immediately following implantation (green, 2662 ± 486 Ω, n = 28 electrodes) and stentrode in vivo with electrodes shorted to the stent (red, 659 ± 113 Ω, n = 7 electrodes). Dashed black line at 1 kΩ indicates in vivo electrode exclusion criteria for viability.
Supplementary Figure 7 Equivalent circuit model of electrode-tissue interface in comparison to saline bath and in vivo measurements
a, Simple equivalent circuit model showing solution resistance (RS), electrode-tissue interface charge transfer resistance (RE) and double-layer capacitance constant phase element (CPEE), and the tissue resistance (RT) and capacitance (CT). b, Comparison between equivalent circuit model impedance (dashed black line) and phase (dotted black line) and electrochemical impedance spectroscopy measurements [mean ± 95%CI] of average impedance (red) and phase angle (blue) of stentrodes immersed in saline (n = 39 electrodes) and in vivo at c, Day 0 (n = 28 electrodes) and d, Day 28 (n=33 electrodes). e, Change in α (black trace) and capacitive magnitude (F, blue trace) of the constant phase element as a function of implant duration, suggestive of incorporation and adherence of proteins to the electrode-tissue interface.
a, Endovascular stent-electrode array (stentrode) is shown implanted within the superior sagittal sinus within the brain. b, The electrode lead wire is shown to exit the brain within the internal jugular vein. c, The lead wire protrudes through the wall of the common jugular vein in the neck, and tunnels subcutaneously to (d) a custom-made hermetic connector secured to a muscle, and exiting the skin in a percutaneous micro circular plug (Omnetics, Minneapolis MN, USA). e,f, Two ground electrodes implanted subcutaneously: a large, stainless steel ground electrode implanted in the back of the sheep (e), and a platinum c-shaped ground electrode under the scalp in close proximity to the stentrode (f). Electrode lead wires and ground electrodes are connected to omnetics connectors (g) that are connected to a data acquisition system (TMSi Porti, Twente Medical Systems International, Oldenzaal, Netherlands) (h) and computer (i) to record neural information.
a, Histogram of all rectified peak latencies (n = 703 peaks, n = 5 animals, n= 57 [40-70] trials/session [median, interquartile range]) demonstrating occurrence of physiological peaks at 20 ms, 28 ms, 38 ms and 51 ms. b-d, Representative SSEP morphologies from individual subjects by individual electrode (b, S4; c, S2; d, S3; e, S1). Insert image displays the distribution of electrodes per subject within the superior sagittal sinus (blue circles, functional and represented electrodes). Blue dashed line represents phase reversal and dipole between peaks. Scale bar, 40 μV, 20 ms.
a, Image plot of the correlation coefficients between electrodes for an example subject. Electrodes (n = 6) on the rostral end of the electrode were positively correlated with each other (yellow, > 0.5), with signals on the caudal end of the array exhibiting a phase shift reflected in the negative correlation coefficients (blue, < 0). b, Correlation coefficients of electrodes (n = 6) from an example subject (mean, SEM) showing a positive to negative change in correlation coefficient indicative of electrode location and phase shift of the acquired signal. c, Population average [mean] image plot of the correlation coefficients (n = 31 electrodes in 5 animals) showing electrodes with high correlation (yellow, >0.2) and low correlation (blue, < 0). The maximum of the color scale has been reduced to 0.45 to allow for easier comparisons, however coefficients for all electrodes against themselves (diagonal values) are 1.
Representative example demonstrating x-ray of co-implanted stentrode (yellow arrow) and epidural array (green arrow) for validation recording acute experiments. Scale bar, 5 mm.
Individual raw ECoG recordings from a, epidural (ED, orange), b, endovascular stentrode (ST, green) and c, subdural (SD, blue) electrode arrays. Red boxes indicate the identified chewing artifacts and the brown boxes indicate the baseline period. Scale bar, 50 µV, 500 ms. d, Artifact-to-baseline ratio for the epidural arrays (2.2 ± 0.1, n = 29 electrodes in 3 sheep), stentrode arrays (2 ± 0.1 [mean ± SE] n = 49 electrodes in 11 sheep) and subdural arrays (1.8 ± 0.1, n = 30 electrodes in 6 sheep). A Tukey-corrected one-way ANOVA showed that there was no statistically significant difference between the subdural, epidural, or stentrode arrays (p=0.109).
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Oxley, T., Opie, N., John, S. et al. Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity. Nat Biotechnol 34, 320–327 (2016). https://doi.org/10.1038/nbt.3428
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