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The endovascular neural interface provides an appealing minimally invasive alternative to invasive brain electrodes for recording and stimulation. However, stents placed in blood vessels have long been known to affect blood flow (haemodynamics) and lead to neointimal growth within the blood vessel. Both the stent elements (struts and electrodes) and blood vessel wall geometries can affect the mechanical environment on the blood vessel wall, which could lead to unfavourable vascular remodelling after stent placement. With increasing applications of stents and stent-like neural interfaces in venous blood vessels in the brain, it is necessary to understand how stents affect blood flow and tissue growth in veins. We explored the haemodynamics of a stent-mounted neural interface in a blood vessel model. Results indicated that blood vessel deformation and tapering caused a substantial change to the lumen geometry and the haemodynamics. The neointimal proliferation was evaluated in sheep implanted with an endovascular neural interface. Analysis showed a negative correlation with the mean Wall Shear Stress pattern. The results presented here indicate that the optimal stent oversizing ratio must be considered to minimise the haemodynamic impact of stenting., (© 2024. The Author(s).)

Stroke is a leading cause of paralysis, most frequently affecting the upper limbs and vocal folds. Despite recent advances in care, stroke recovery invariably reaches a plateau, after which there are permanent neurological impairments. Implantable brain-computer interface devices offer the potential to bypass permanent neurological lesions. They function by (1) recording neural activity, (2) decoding the neural signal occurring in response to volitional motor intentions, and (3) generating digital control signals that may be used to control external devices. While brain-computer interface technology has the potential to revolutionize neurological care, clinical translation has been limited. Endovascular arrays present a novel form of minimally invasive brain-computer interface devices that have been deployed in human subjects during early feasibility studies. This article provides an overview of endovascular brain-computer interface devices and critically evaluates the patient with stroke as an implant candidate. Future opportunities are mapped, along with the challenges arising when decoding neural activity following infarction. Limitations arise when considering intracerebral hemorrhage and motor cortex lesions; however, future directions are outlined that aim to address these challenges., Competing Interests: Disclosures Drs Fry, Opie, and Oxley are employees of Synchron. Drs Fry, Opie, and Oxley report stock options from Synchron. Dr Brannigan reports consulting fees from Synchron. Drs Opie and Oxley report issued and pending patents for sensing or stimulating activity of neural tissue. P. Mitchell reports compensation from Stryker Corporation for consultant services; compensation from Medtronic USA, Inc, and Stryker Corporation for other services. The other author reports no conflicts.

Importance: Brain-computer interface (BCI) implants have previously required craniotomy to deliver penetrating or surface electrodes to the brain. Whether a minimally invasive endovascular technique to deliver recording electrodes through the jugular vein to superior sagittal sinus is safe and feasible is unknown., Objective: To assess the safety of an endovascular BCI and feasibility of using the system to control a computer by thought., Design, Setting, and Participants: The Stentrode With Thought-Controlled Digital Switch (SWITCH) study, a single-center, prospective, first in-human study, evaluated 5 patients with severe bilateral upper-limb paralysis, with a follow-up of 12 months. From a referred sample, 4 patients with amyotrophic lateral sclerosis and 1 with primary lateral sclerosis met inclusion criteria and were enrolled in the study. Surgical procedures and follow-up visits were performed at the Royal Melbourne Hospital, Parkville, Australia. Training sessions were performed at patients' homes and at a university clinic. The study start date was May 27, 2019, and final follow-up was completed January 9, 2022., Interventions: Recording devices were delivered via catheter and connected to subcutaneous electronic units. Devices communicated wirelessly to an external device for personal computer control., Main Outcomes and Measures: The primary safety end point was device-related serious adverse events resulting in death or permanent increased disability. Secondary end points were blood vessel occlusion and device migration. Exploratory end points were signal fidelity and stability over 12 months, number of distinct commands created by neuronal activity, and use of system for digital device control., Results: Of 4 patients included in analyses, all were male, and the mean (SD) age was 61 (17) years. Patients with preserved motor cortex activity and suitable venous anatomy were implanted. Each completed 12-month follow-up with no serious adverse events and no vessel occlusion or device migration. Mean (SD) signal bandwidth was 233 (16) Hz and was stable throughout study in all 4 patients (SD range across all sessions, 7-32 Hz). At least 5 attempted movement types were decoded offline, and each patient successfully controlled a computer with the BCI., Conclusions and Relevance: Endovascular access to the sensorimotor cortex is an alternative to placing BCI electrodes in or on the dura by open-brain surgery. These final safety and feasibility data from the first in-human SWITCH study indicate that it is possible to record neural signals from a blood vessel. The favorable safety profile could promote wider and more rapid translation of BCI to people with paralysis., Trial Registration: ClinicalTrials.gov Identifier: NCT03834857.

Objective. The aim of this work was to assess vascular remodeling after the placement of an endovascular neural interface (ENI) in the superior sagittal sinus (SSS) of sheep. We also assessed the efficacy of neural recording using an ENI. Approach. The study used histological analysis to assess the composition of the foreign body response. Micro-CT images were analyzed to assess the profiles of the foreign body response and create a model of a blood vessel. Computational fluid dynamic modeling was performed on a reconstructed blood vessel to evaluate the blood flow within the vessel. Recording of brain activity in sheep was used to evaluate efficacy of neural recordings. Main results. Histological analysis showed accumulated extracellular matrix material in and around the implanted ENI. The extracellular matrix contained numerous macrophages, foreign body giant cells, and new vascular channels lined by endothelium. Image analysis of CT slices demonstrated an uneven narrowing of the SSS lumen proportional to the stent material within the blood vessel. However, the foreign body response did not occlude blood flow. The ENI was able to record epileptiform spiking activity with distinct spike morphologies. Significance . This is the first study to show high-resolution tissue profiles, the histological response to an implanted ENI and blood flow dynamic modeling based on blood vessels implanted with an ENI. The results from this study can be used to guide surgical planning and future ENI designs; stent oversizing parameters to blood vessel diameter should be considered to minimize detrimental vascular remodeling., (Creative Commons Attribution license.)

Over the last few decades, biomedical implants have successfully delivered therapeutic electrical stimulation to reduce the frequency and severity of seizures in people with drug-resistant epilepsy. However, neurostimulation approaches require invasive surgery to implant stimulating electrodes, and surgical, medical, and hardware complications are not uncommon. An endovascular approach provides a potentially safer and less invasive surgical alternative. This article critically evaluates the feasibility of endovascular closed-loop neuromodulation for the treatment of epilepsy. By reviewing literature that reported the impact of direct electrical stimulation to reduce the frequency of epileptic seizures, we identified clinically validated extracranial, cortical, and deep cortical neural targets. We identified veins in close proximity to these targets and evaluated the potential of delivering an endovascular implant to these veins based on their diameter. We then compared the risks and benefits of existing technology to describe a benchmark of clinical safety and efficacy that would need to be achieved for endovascular neuromodulation to provide therapeutic benefit. For the majority of brain regions that have been clinically demonstrated to reduce seizure occurrence in response to delivered electrical stimulation, vessels of appropriate diameter for delivery of an endovascular electrode to these regions could be achieved. This includes delivery to the vagus nerve via the 13.2 ± 0.9 mm diameter internal jugular vein, the motor cortex via the 6.5 ± 1.7 mm diameter superior sagittal sinus, and the cerebellum via the 7.7 ± 1.4 mm diameter sigmoid sinus or 6.2 ± 1.4 mm diameter transverse sinus. Deep cerebral targets can also be accessed with an endovascular approach, with the 1.9 ± 0.5 mm diameter internal cerebral vein and 1.2-mm-diameter thalamostriate vein lying in close proximity to the anterior and centromedian nuclei of the thalamus, respectively. This work identified numerous veins that are in close proximity to conventional stimulation targets that are of a diameter large enough for delivery and deployment of an endovascular electrode array, supporting future work to assess clinical efficacy and chronic safety of an endovascular approach to deliver therapeutic neurostimulation., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Aim: Brain-Computer Interfaces (BCIs) hold promise to provide people with partial or complete paralysis, the ability to control assistive technology. This study reports offline classification of imagined and executed movements of the upper and lower limb in one participant with multiple sclerosis and people with no limb function deficits., Methods: We collected neural signals using electroencephalography (EEG) while participants performed executed and imagined motor tasks as directed by prompts shown on a screen., Results: Participants with no limb function attained >70% decoding accuracy on their best-imagined task compared to rest and on at-least one task comparison. The participant with multiple sclerosis also achieved accuracies within the range of participants with no limb function loss.Clinical Relevance - While only one case study is provided it was promising that the participant with MS was able to achieve comparable classification to that of the seven healthy controls. Further studies are needed to assess whether people suffering from MS may be able to use a BCI to improve their quality of life.

Background: Implantable brain-computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore voluntary motor impulses to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. However, reports to date have had limited clinical translation., Methods: Two participants with amyotrophic lateral sclerosis (ALS) underwent implant in a single-arm, open-label, prospective, early feasibility study. Using a minimally invasive neurointervention procedure, a novel endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. The participants undertook machine-learning-assisted training to use wirelessly transmitted electrocorticography signal associated with attempted movements to control multiple mouse-click actions, including zoom and left-click. Used in combination with an eye-tracker for cursor navigation, participants achieved Windows 10 operating system control to conduct instrumental activities of daily living (IADL) tasks., Results: Unsupervised home use commenced from day 86 onwards for participant 1, and day 71 for participant 2. Participant 1 achieved a typing task average click selection accuracy of 92.63% (100.00%, 87.50%-100.00%) (trial mean (median, Q1-Q3)) at a rate of 13.81 (13.44, 10.96-16.09) correct characters per minute (CCPM) with predictive text disabled. Participant 2 achieved an average click selection accuracy of 93.18% (100.00%, 88.19%-100.00%) at 20.10 (17.73, 12.27-26.50) CCPM. Completion of IADL tasks including text messaging, online shopping and managing finances independently was demonstrated in both participants., Conclusion: We describe the first-in-human experience of a minimally invasive, fully implanted, wireless, ambulatory motor neuroprosthesis using an endovascular stent-electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices in two participants with flaccid upper limb paralysis., Competing Interests: Competing interests: TJO reports stock options from Synchron, during the conduct of the study; in addition, TJO has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending. PEY reports stock options from Synchron, during the conduct of the study; in addition, PEY has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending. GSR reports stock options from Synchron, during the conduct of the study; in addition, GSR has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending. SMR reports stock options from Synchron, during the conduct of the study; in addition, SMR has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending. RPS reports stock options from Synchron, during the conduct of the study. VH reports personal fees from Synchron, during the conduct of the study. LRH reports that The Massachusetts General Hospital (MGH) Translational Research Center (TRC) has clinical research support agreements with Synchron, Paradromics and Neuralink, for which LRH provides consultative input. TD reports personal fees from Synchron, during the conduct of the study. JM reports stock options from Synchron, during the conduct of the study. NLO reports stock options from Synchron, during the conduct of the study; in addition, NLO has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Due to their increased proximity to retinal ganglion cells (RGCs), epiretinal visual prostheses present the opportunity for eliciting phosphenes with low thresholds through direct RGC activation. This study characterised the in vivo performance of a novel prototype monolithic epiretinal prosthesis, containing Nitrogen incorporated ultrananocrystalline (N-UNCD) diamond electrodes., Approach: A prototype implant containing up to twenty-five 120 × 120 µm N-UNCD electrodes was implanted into 16 anaesthetised cats and attached to the retina either using a single tack or via magnetic coupling with a suprachoroidally placed magnet. Multiunit responses to retinal stimulation using charge-balanced biphasic current pulses were recorded acutely in the visual cortex using a multichannel planar array. Several stimulus parameters were varied including; the stimulating electrode, stimulus polarity, phase duration, return configuration and the number of electrodes stimulated simultaneously., Main Results: The rigid nature of the device and its form factor necessitated complex surgical procedures. Surgeries were considered successful in 10/16 animals and cortical responses to single electrode stimulation obtained in eight animals. Clinical imaging and histological outcomes showed severe retinal trauma caused by the device in situ in many instances. Cortical measures were found to significantly depend on the surgical outcomes of individual experiments, phase duration, return configuration and the number of electrodes stimulated simultaneously, but not stimulus polarity. Cortical thresholds were also found to increase over time within an experiment., Significance: The study successfully demonstrated that an epiretinal prosthesis containing diamond electrodes could produce cortical activity with high precision, albeit only in a small number of cases. Both surgical approaches were highly challenging in terms of reliable and consistent attachment to and stabilisation against the retina, and often resulted in severe retinal trauma. There are key challenges (device form factor and attachment technique) to be resolved for such a device to progress towards clinical application, as current surgical techniques are unable to address these issues.

There is evidence to suggest that motor execution and motor imagery both involve planning and execution of the same motor plan, however, in the latter the output is inhibited. Currently, little is known about the underlying neural mechanisms of motor output inhibition during motor imagery. Uncovering the distinctive characteristics of motor imagery may help us better understand how we abstract complex thoughts and acquire new motor skills. The current study aimed to dissociate the cognitive processes involved in two distinct inhibitory mechanisms of motor inhibition and motor imagery restraint. Eleven healthy participants engaged in an imagined GO/NO-GO task during a 7 Tesla fMRI experiment. Participants planned a specific type of motor imagery, then, imagined the movements during the GO condition and restrained from making a response during the NO-GO condition. The results revealed that specific sub-regions of the supplementary motor cortex (SMC) and the primary motor cortex (M1) were recruited during the imagination of specific movements and information flowed from the SMC to the M1. Such condition-specific recruitment was not observed when motor imagery was restrained. Instead, general recruitment of the posterior parietal cortex (PPC) was observed, while the BOLD activity in the SMC and the M1 decreased below the baseline at the same time. Information flowed from the PPC to the SMC, and recurrently between the M1 and the SMC, and the M1 and the PPC. These results suggest that motor imagery involves task-specific motor output inhibition partly imposed by the SMC to the M1, while the PPC globally inhibits motor plans before they are passed on for execution during the restraint of responses., (Copyright © 2020 Yoo, Oxley, Hagan, John, Ronayne, Rind, Brinded, Opie, Moffat and Wong.)

Endovascular neuromodulation is an emerging technology that represents a synthesis between interventional neurology and neural engineering. The prototypical endovascular neural interface is the Stentrode TM , a stent-electrode array which can be implanted into the superior sagittal sinus via percutaneous catheter venography, and transmits signals through a transvenous lead to a receiver located subcutaneously in the chest. Whilst the Stentrode TM has been conceptually validated in ovine models, questions remain about the long term viability and safety of this device in human recipients. Although technical precedence for venous sinus stenting already exists in the setting of idiopathic intracranial hypertension, long term implantation of a lead within the intracranial veins has never been previously achieved. Contrastingly, transvenous leads have been successfully employed for decades in the setting of implantable cardiac pacemakers and defibrillators. In the current absence of human data on the Stentrode TM , the literature on these structurally comparable devices provides valuable lessons that can be translated to the setting of endovascular neuromodulation. This review will explore this literature in order to understand the potential risks of the Stentrode TM and define avenues where further research and development are necessary in order to optimize this device for human application., (Copyright © 2020 Raza, Opie, Morokoff, Sharma, Mitchell and Oxley.)

Brain-computer interface (BCI) technology is rapidly developing and changing the paradigm of neurorestoration by linking cortical activity with control of an external effector to provide patients with tangible improvements in their ability to interact with the environment. The sensor component of a BCI circuit dictates the resolution of brain pattern recognition and therefore plays an integral role in the technology. Several sensor modalities are currently in use for BCI applications and are broadly either electrode-based or functional neuroimaging-based. Sensors vary in their inherent spatial and temporal resolutions, as well as in practical aspects such as invasiveness, portability, and maintenance. Hybrid BCI systems with multimodal sensory inputs represent a promising development in the field allowing for complimentary function. Artificial intelligence and deep learning algorithms have been applied to BCI systems to achieve faster and more accurate classifications of sensory input and improve user performance in various tasks. Neurofeedback is an important advancement in the field that has been implemented in several types of BCI systems by showing users a real-time display of their recorded brain activity during a task to facilitate their control over their own cortical activity. In this way, neurofeedback has improved BCI classification and enhanced user control over BCI output. Taken together, BCI systems have progressed significantly in recent years in terms of accuracy, speed, and communication. Understanding the sensory components of a BCI is essential for neurosurgeons and clinicians as they help advance this technology in the clinical setting., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Objective: Neural prostheses are improving the quality of life for those suffering from neurological impairments. Electrocorticography electrodes located in subdural, epidural, and intravascular positions show promise as long-term neural prostheses. However, chronic implantation affects the electrochemical environments of these arrays., Methods: In the present work, the effect of electrode location on the electrochemical properties of the interface was compared. The impedances of the electrode arrays were measured using electrochemical impedance spectroscopy in vitro in saline and in vivo four-week postimplantation., Results: There was not a significant effect of electrode location (subdural, intravascular, or epidural) on the impedance magnitude, and the effect of the electrode size on the impedance magnitude was frequency dependent. There was a frequency-dependent statistically significant effect of electrode location and electrode size on the phase angles of the three arrays. The subdural and epidural arrays showed phase shifts closer to -90° indicating the capacitive nature of the interface in these locations. The impact of placing electrodes within a blood vessel and adjacent to the blood vessel wall was most obvious when looking at the phase responses at frequencies below 10 kHz., Conclusion: Our results show that intravascular electrodes, like those in subdural and epidural positions, show electrical properties that are suitable for recording. These results provide support for the use of intravascular arrays in clinically relevant neural prostheses and diagnostic devices., Significance: Comparison of electrochemical impedance of the epidural, intravascular, and subdural electrode array showed that all three locations are possible placement options, since impedances are in comparable ranges.

Direct electrical stimulation of the brain can alleviate symptoms associated with Parkinson's disease, depression, epilepsy and other neurological disorders. However, access to the brain requires invasive procedures, such as the removal of a portion of the skull or the drilling of a burr hole. Also, electrode implantation into tissue can cause inflammatory tissue responses and brain trauma, and lead to device failure. Here, we report the development and application of a chronically implanted platinum electrode array mounted on a nitinol endovascular stent for the localized stimulation of cortical tissue from within a blood vessel. Following percutaneous angiographic implantation of the device in sheep, we observed stimulation-induced responses of the facial muscles and limbs of the animals, similar to those evoked by electrodes implanted via invasive surgery. Proximity of the electrode to the motor cortex, yet not its orientation, was integral to achieving reliable responses from discrete neuronal populations. The minimally invasive endovascular surgical approach offered by the stent-mounted electrode array might enable safe and efficacious stimulation of focal regions in the brain.

Invasive Brain-Computer Interfaces (BCIs) require surgeries with high health-risks. The risk-to-benefit ratio of the procedure could potentially be improved by pre-surgically identifying the ideal locations for mental strategy classification. We recorded high-spatiotemporal resolution blood-oxygenation-level-dependent (BOLD) signals using functional MRI at 7 Tesla in eleven healthy participants during two motor imagery tasks. BCI diagnostic task isolated the intent to imagine movements, while BCI simulation task simulated the neural states that may be yielded in a real-life BCI-operation scenario. Imagination of movements were classified from the BOLD signals in sub-regions of activation within a single or multiple dorsal motor network regions. Then, the participant's decoding performance during the BCI simulation task was predicted from the BCI diagnostic task. The results revealed that drawing information from multiple regions compared to a single region increased the classification accuracy of imagined movements. Importantly, systematic unimodal and multimodal classification revealed the ideal combination of regions that yielded the best classification accuracy at the individual-level. Lastly, a given participant's decoding performance achieved during the BCI simulation task could be predicted from the BCI diagnostic task. These results show the feasibility of 7T-fMRI with unimodal and multimodal classification being utilized for identifying ideal sites for mental strategy classification.

Objective: Ultra-high-field functional MRI (UHF-fMRI) allows for higher spatiotemporal resolution imaging. However, higher-resolution imaging entails coverage limitations. Processing partial-coverage images using standard pipelines leads to sub-optimal results. We aimed to develop a simple, semi-automated pipeline for processing partial-coverage UHF-fMRI data using widely used image processing algorithms., Materials and Methods: We developed automated pipelines for optimized skull stripping and co-registration of partial-coverage UHF functional images, using built-in functions of the Centre for Functional Magnetic Resonance Imaging of the Brain's (FMRIB's) Software library (FSL) and advanced normalization tools. We incorporated the pipelines into the FSL's functional analysis pipeline and provide a semi-automated optimized partial-coverage functional analysis pipeline (OPFAP)., Results: Compared to the standard pipeline, the OPFAP yielded images with 15 and 30% greater volume of non-zero voxels after skull stripping the functional and anatomical images, respectively (all p = 0.0004), which reflected the conservation of cortical voxels lost when the standard pipeline was used. The OPFAP yielded the greatest Dice and Jaccard coefficients (87 and 80%, respectively; all p < 0.0001) between the co-registered participant gyri maps and the template gyri maps, demonstrating the goodness of the co-registration results. Furthermore, the greatest volume of group-level activation in the most number of functionally relevant regions was observed when the OPFAP was used. Importantly, group-level activations were not observed when using the standard pipeline., Conclusion: These results suggest that the OPFAP should be used for processing partial-coverage UHF-fMRI data for detecting high-resolution macroscopic blood oxygenation level-dependent activations.

Electrical stimulation of neural tissue and recording of neural activity are the bases of emerging prostheses and treatments for spinal cord injury, stroke, sensory deficits, and drug-resistant neurological disorders. Safety and efficacy are key aspects for the clinical acceptance of therapeutic neural stimulators. The cortical vasculature has been shown to be a safe site for implantation of electrodes for chronically recording neural activity, requiring no craniotomy to access high-bandwidth, intracranial EEG. This work presents the first characterization of endovascular cortical stimulation measured using cortical subdural surface recordings. Visual stimulation was used to verify electrode viability and cortical activation was compared with electrically evoked activity. Due to direct activation of the neural tissue, the latency of responses to electrical stimulation was shorter than for that of visual stimulation. We also found that the center of neural activation was different for visual and electrical stimulation indicating an ability of the stentrode to provide localized activation of neural tissue.

Access to the brain to implant recording electrodes has conventionally required a craniotomy. To mitigate risks of open brain surgery, we previously developed a stent-electrode array that can be delivered to the cortex via cerebral vessels. Following implantation of a stent-electrode array (Stentrode) in a large animal model, we investigated the longevity of highquality signals, by measuring bandwidth in animals implanted for up to six months; no signal degradation was observed. We also investigated whether bandwidth was influenced by implant location with respect to the superior sagittal sinus and branching cortical veins; it was not. Finally, we assessed whether electrode orientation had an impact on recording quality. There was no significant difference in bandwidths from electrodes facing different orientations. Interestingly, electrodes facing the skull (180°) were still able to record neural information with high fidelity. Consequently, a minimally invasive surgical approach combined with a stent-electrode array is a safe and efficacious technique to acquire neural signals over a chronic duration.

Performing voluntary movements involves many regions of the brain, but it is unknown how they work together to plan and execute specific movements. We recorded high-resolution ultra-high-field blood-oxygen-level-dependent signal during a cued ankle-dorsiflexion task. The spatiotemporal dynamics and the patterns of task-relevant information flow across the dorsal motor network were investigated. We show that task-relevant information appears and decays earlier in the higher order areas of the dorsal motor network then in the primary motor cortex. Furthermore, the results show that task-relevant information is encoded in general initially, and then selective goals are subsequently encoded in specifics subregions across the network. Importantly, the patterns of recurrent information flow across the network vary across different subregions depending on the goal. Recurrent information flow was observed across all higher order areas of the dorsal motor network in the subregions encoding for the current goal. In contrast, only the top-down information flow from the supplementary motor cortex to the frontoparietal regions, with weakened recurrent information flow between the frontoparietal regions and bottom-up information flow from the frontoparietal regions to the supplementary cortex were observed in the subregions encoding for the opposing goal. We conclude that selective motor goal encoding and execution rely on goal-dependent differences in subregional recurrent information flow patterns across the long-range dorsal motor network areas that exhibit graded functional specialization., (© 2018 Wiley Periodicals, Inc.)

Recent work has demonstrated the feasibility of minimally-invasive implantation of electrodes into a cortical blood vessel. However, the effect of the dura and blood vessel on recording signal quality is not understood and may be a critical factor impacting implementation of a closed-loop endovascular neuromodulation system. The present work compares the performance and recording signal quality of a minimally-invasive endovascular neural interface with conventional subdural and epidural interfaces. We compared bandwidth, signal-to-noise ratio, and spatial resolution of recorded cortical signals using subdural, epidural and endovascular arrays four weeks after implantation in sheep. We show that the quality of the signals (bandwidth and signal-to-noise ratio) of the endovascular neural interface is not significantly different from conventional neural sensors. However, the spatial resolution depends on the array location and the frequency of recording. We also show that there is a direct correlation between the signal-noise-ratio and classification accuracy, and that decoding accuracy is comparable between electrode arrays. These results support the consideration for use of an endovascular neural interface in a clinical trial of a novel closed-loop neuromodulation technology.

OBJECTIVE Neural interface technology may enable the development of novel therapies to treat neurological conditions, including motor prostheses for spinal cord injury. Intracranial neural interfaces currently require a craniotomy to achieve implantation and may result in chronic tissue inflammation. Novel approaches are required that achieve less invasive implantation methods while maintaining high spatial resolution. An endovascular stent electrode array avoids direct brain trauma and is able to record electrocorticography in local cortical tissue from within the venous vasculature. The motor area in sheep runs in a parasagittal plane immediately adjacent to the superior sagittal sinus (SSS). The authors aimed to develop a sheep model of cerebral venography that would enable validation of an endovascular neural interface. METHODS Cerebral catheter venography was performed in 39 consecutive sheep. Contrast-enhanced MRI of the brain was performed on 13 animals. Multiple telescoping coaxial catheter systems were assessed to determine the largest wide-bore delivery catheter that could be delivered into the anterior SSS. Measurements of SSS diameter and distance from the motor area were taken. The location of the motor area was determined in relation to lateral and superior projections of digital subtraction venography images and confirmed on MRI. RESULTS The venous pathway from the common jugular vein (7.4 mm) to the anterior SSS (1.2 mm) was technically challenging to selectively catheterize. The SSS coursed immediately adjacent to the motor cortex (< 1 mm) for a length of 40 mm, or the anterior half of the SSS. Attempted access with 5-Fr and 6-Fr delivery catheters was associated with longer procedure times and higher complication rates. A 4-Fr catheter (internal lumen diameter 1.1 mm) was successful in accessing the SSS in 100% of cases with no associated complications. Complications included procedure-related venous dissection in two major areas: the torcular herophili, and the anterior formation of the SSS. The bifurcation of the cruciate sulcal veins with the SSS was a reliable predictor of the commencement of the motor area. CONCLUSIONS The ovine model for cerebral catheter venography has generalizability to the human cerebral venous system in relation to motor cortex location. This novel model may facilitate the development of the novel field of endovascular neural interfaces that may include preclinical investigations for cortical recording applications such as paralysis and epilepsy, as well as other potential applications in neuromodulation.

Recent developments in accelerated imaging methods allow faster acquisition of high spatial resolution images. This could improve the applications of functional magnetic resonance imaging at 7 Tesla (7T-fMRI), such as neurosurgical planning and Brain Computer Interfaces (BCIs). However, increasing the spatial and temporal resolution will both lead to signal-to-noise ratio (SNR) losses due to decreased net magnetization per voxel and T 1 -relaxation effect, respectively. This could potentially offset the SNR efficiency gains made with increasing temporal resolution. We investigated the effects of varying spatial and temporal resolution on fMRI sensitivity measures and their implications on fMRI-based BCI simulations. We compared temporal signal-to-noise ratio (tSNR), observed percent signal change (%∆S), volumes of significant activation, Z-scores and decoding performance of linear classifiers commonly used in BCIs across a range of spatial and temporal resolution images acquired during an ankle-tapping task. Our results revealed an average increase of 22% in %∆S (p=0.006) and 9% in decoding performance (p=0.015) with temporal resolution only at the highest spatial resolution of 1.5×1.5×1.5mm 3 , despite a 29% decrease in tSNR (p<0.001) and plateaued Z-scores. Further, the volume of significant activation was indifferent (p>0.05) across spatial resolution specifically at the highest temporal resolution of 500ms. These results demonstrate that the overall BOLD sensitivity can be increased significantly with temporal resolution, granted an adequately high spatial resolution with minimal physiological noise level. This shows the feasibility of diffuse motor-network imaging at high spatial and temporal resolution with robust BOLD sensitivity with 7T-fMRI. Importantly, we show that this sensitivity improvement could be extended to an fMRI application such as BCIs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In recent years, sheep (Ovis aries) have emerged as a useful animal model for neurological research due to their relatively large brain and blood vessel size, their cortical architecture, and their docile temperament. However, the functional anatomy of sheep brain is not as well studied as that of non-human primates, rodents, and felines. For example, while the location of the sheep motor cortex has been known for many years, there have been few studies of the somatotopy of the motor cortex and there were a range of discrepancies across them. The motivation for this review is to provide a definitive resource for studies of the sheep motor cortex. This work critically reviews the literature examining the organization of the motor cortex in sheep, utilizing studies that have applied direct electrical stimulation and histological methods A clearer understanding of the sheep brain will facilitate and progress the use of this species as a scientific animal model for neurological research., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Intracranial atherosclerosis is a major cause of ischemic stroke. Patients with a high degree of stenosis have a significant rate of stroke despite medical therapy. Two randomized trials of stenting have failed to show benefit. Improving periprocedural complication rates and patient selection may improve stenting outcomes. Fractional flow reserve (FFR), intravascular ultrasound (IVUS), and optical coherence tomography (OCT) are intravascular imaging techniques employed to improve patient selection and stent placement in interventional cardiology. FFR has been shown to improve cardiovascular outcomes when used in patient selection for intervention. Studies of FFR in intracranial atherosclerosis show that the measure may predict which plaques lead to stroke. IVUS is used in cardiology to quantify stenosis and assist with stent placement. Comparisons with histology show that it can reliably characterize plaques. Several case reports of IVUS in intracranial arteries show the technique to be feasible and indicate it may improve stent placement. Plaque characteristics on IVUS may help identify vulnerable plaques. In interventional cardiology, OCT provides excellent visualization of vessel geometry and is useful periprocedurally. Images reliably identify thin-capped fibroatheromas and other plaque features. Case reports indicate that OCT is safe for use in intracranial arteries. OCT can be used to identify perforator vessels and so may be useful in avoiding perforator strokes, a common complication of stenting. Plaque characteristics on OCT may be useful in patient selection.

Objective: Recently, we reported the development of a stent-mounted electrode array (Stentrode) capable of chronically recording neural signals from within a blood vessel with high fidelity. Preliminary data suggested incorporation of the Stentrode into the blood vessel wall was associated with improved recording sensitivity. We now investigate neointimal incorporation of the Stentrode, implanted in a cohort of sheep for up to 190 days., Methods: Micro-CT, obtained from the Imaging and Medical Beamline at the Australian Synchrotron, and histomorphometic techniques developed specifically for evaluation of cerebral vasculature implanted with a stent-electrode array were compared as measures to assess device incorporation and vessel patency., Results: Both micro-CT analysis and histomorphometry, revealed a strong correlation between implant duration and the number of incorporated stent struts. <10% (26/268) of stent struts were covered in neointima in sheep implanted for <2 weeks, increasing to >78% (191/243) between 2 and 4 weeks. Average strut-to-lumen thickness from animals implanted >12 weeks was comparable across both modalities, 339 ±15 μm measured using micro-CT and 331 ±19 μm ( n = 292) measured histologically. There was a strong correlation between lumen areas measured using the two modalities ( ), with no observation of vessel occlusion observed from any of the 12 animals implanted for up to 190 days., Conclusion: Micro-CT and the histomorphometric techniques we developed are comparable and can both be used to identify incorporation of a Stentrode implanted in cerebral vessels., Significance: This study demonstrates preliminary safety of a stent-electrode array implanted in cerebral vasculature, which may facilitate technological advances in minimally invasive brain-computer interfaces.

Development of a neural interface that can be implanted without risky, open brain surgery will increase the safety and viability of chronic neural recording arrays. We have developed a minimally invasive surgical procedure and an endovascular electrode-array that can be delivered to overlie the cortex through blood vessels. Here, we describe feasibility of the endovascular interface through electrode viability, recording potential and safety. Electrochemical impedance spectroscopy demonstrated that electrode impedance was stable over 91 days and low frequency phase could be used to infer electrode incorporation into the vessel wall. Baseline neural recording were used to identify the maximum bandwidth of the neural interface, which remained stable around 193 Hz for six months. Cross-sectional areas of the implanted vessels were non-destructively measured using the Australian Synchrotron. There was no case of occlusion observed in any of the implanted animals. This work demonstrates the feasibility of an endovascular neural interface to safely and efficaciously record neural information over a chronic time course.

Objective: Recently, we reported a minimally invasive stent-electrode array capable of recording neural signals from within a blood vessel. We now investigate the use of electrochemical impedance spectroscopy (EIS) measurements to infer changes occurring to the electrode-tissue interface from devices implanted in a cohort of sheep for up to 190 days., Approach: In a cohort of 15 sheep, endovascular stent-electrode arrays were implanted in the superior sagittal sinus overlying the motor cortex for up to 190 days. EIS was performed routinely to quantify viable electrodes for up to 91 days. An equivalent circuit model (ECM) was developed from the in vivo measurements to characterize the electrode-tissue interface changes occurring to the electrodes chronically implanted within a blood vessel. Post-mortem histological assessment of stent and electrode incorporation into the wall of the cortical vessels was compared to the electrical impedance measurements., Main Results: EIS could be used to infer electrode viability and was consistent with x-ray analysis performed in vivo, and post-mortem evaluation. Viable electrodes exhibited consistent 1 kHz impedances across the 91 day measurement period, with the peak resistance frequency for the acquired data also stable over time. There was a significant change in 100 Hz phase angles, increasing from -67.8° ± 8.8° at day 0 to -43.8° ± 0.8° at day 91, which was observed to stabilize after eight days. ECM's modeled to the data suggested this change was due to an increase in the capacitance of the electrode-tissue interface. This was supported by histological assessment with >85% of the implanted stent struts covered with neointima and incorporated into the blood vessel within two weeks., Conclusion: This work demonstrated that EIS could be used to determine the viability of electrode implanted chronically within a blood vessel. Impedance measurements alone were not observed to be a useful predictor of alterations occurring at the electrode tissue interface. However, measurement of 100 Hz phase angles was in good agreement with the capacitive changes predicted by the ECM and consistent with suggestions that this represents protein absorption on the electrode surface. 100 Hz phase angles stabilized after 8 days, consistent with histologically assessed samples., Significance: These findings demonstrate the potential application of this technology for use as a chronic neural recording system and indicate the importance of conducting EIS as a measure to identify viable electrodes and changes occurring at the electrode-tissue interface.

A major challenge facing neural prostheses is the development of electrodes that are well tolerated by the brain and body. A novel way to circumvent the need to perform an invasive craniotomy and penetration of the blood-brain barrier to implant electrodes, is to guide electrodes up into the cerebral veins and place electrodes on the vessel walls adjacent to neuronal populations. To aid in the development of these stent based devices, microelectrodes manufactured from Nitinol would allow electrodes to be implanted via a catheter and then once deployed, alter their shape to conform to the vessel walls. However, there is a paucity of data on whether Nitinol is a suitable material to record neural signals. Here we show that Nitinol is tolerated by the body and that it can effectively measure neural signals. Specifically, we electrochemically evaluate Nitinol electrodes in blood and record visually evoked potentials from sheep.

Segmentation is the process of partitioning an image into subdivisions and can be applied to medical images to isolate anatomical or pathological areas for further analysis. This process can be done manually or automated by the use of image processing computer packages. Atlas-based segmentation automates this process by the use of a pre-labelled template and a registration algorithm. We developed an ovine brain atlas that can be used as a model for neurological conditions such as Parkinson's disease and focal epilepsy. 17 female Corriedale ovine brains were imaged in-vivo in a 1.5T (low-resolution) MRI scanner. 13 of the low-resolution images were combined using a template construction algorithm to form a low-resolution template. The template was labelled to form an atlas and tested by comparing manual with atlas-based segmentations against the remaining four low-resolution images. The comparisons were in the form of similarity metrics used in previous segmentation research. Dice Similarity Coefficients were utilised to determine the degree of overlap between eight independent, manual and atlas-based segmentations, with values ranging from 0 (no overlap) to 1 (complete overlap). For 7 of these 8 segmented areas, we achieved a Dice Similarity Coefficient of 0.5-0.8. The amygdala was difficult to segment due to its variable location and similar intensity to surrounding tissues resulting in Dice Coefficients of 0.0-0.2. We developed a low resolution ovine brain atlas with eight clinically relevant areas labelled. This brain atlas performed comparably to prior human atlases described in the literature and to intra-observer error providing an atlas that can be used to guide further research using ovine brains as a model and is hosted online for public access.

Current standard practice requires an invasive approach to the recording of electroencephalography (EEG) for epilepsy surgery, deep brain stimulation (DBS), and brain-machine interfaces (BMIs). The development of endovascular techniques offers a minimally invasive route to recording EEG from deep brain structures. This historical perspective aims to describe the technical progress in endovascular EEG by reviewing the first endovascular recordings made using a wire electrode, which was followed by the development of nanowire and catheter recordings and, finally, the most recent progress in stent-electrode recordings. The technical progress in device technology over time and the development of the ability to record chronic intravenous EEG from electrode arrays is described. Future applications for the use of endovascular EEG in the preoperative and operative management of epilepsy surgery are then discussed, followed by the possibility of the technique's future application in minimally invasive operative approaches to DBS and BMI.

Successful visual prostheses require stable, long-term attachment. Epiretinal prostheses, in particular, require attachment methods to fix the prosthesis onto the retina. The most common method is fixation with a retinal tack; however, tacks cause retinal trauma, and surgical proficiency is important to ensure optimal placement of the prosthesis near the macula. Accordingly, alternate attachment methods are required. In this study, we detail a novel method of magnetic attachment for an epiretinal prosthesis using two prostheses components positioned on opposing sides of the retina. The magnetic attachment technique was piloted in a feline animal model (chronic, nonrecovery implantation). We also detail a new method to reliably control the magnet coupling force using heat. It was found that the force exerted upon the tissue that separates the two components could be minimized as the measured force is proportionately smaller at the working distance. We thus detail, for the first time, a surgical method using customized magnets to position and affix an epiretinal prosthesis on the retina. The position of the epiretinal prosthesis is reliable, and its location on the retina is accurately controlled by the placement of a secondary magnet in the suprachoroidal location. The electrode position above the retina is less than 50 microns at the center of the device, although there were pressure points seen at the two edges due to curvature misalignment. The degree of retinal compression found in this study was unacceptably high; nevertheless, the normal structure of the retina remained intact under the electrodes., (Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

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.

Unlabelled: Retinal visual prostheses ("bionic eyes") have the potential to restore vision to blind or profoundly vision-impaired patients. The medical bionic technology used to design, manufacture and implant such prostheses is still in its relative infancy, with various technologies and surgical approaches being evaluated. We hypothesised that a suprachoroidal implant location (between the sclera and choroid of the eye) would provide significant surgical and safety benefits for patients, allowing them to maintain preoperative residual vision as well as gaining prosthetic vision input from the device. This report details the first-in-human Phase 1 trial to investigate the use of retinal implants in the suprachoroidal space in three human subjects with end-stage retinitis pigmentosa. The success of the suprachoroidal surgical approach and its associated safety benefits, coupled with twelve-month post-operative efficacy data, holds promise for the field of vision restoration., Trial Registration: Clinicaltrials.gov NCT01603576.

Background: Current surgical techniques for retinal prosthetic implantation require long and complicated surgery, which can increase the risk of complications and adverse outcomes., Method: The suprachoroidal position is known to be an easier location to access surgically, and so this study aimed to develop a surgical procedure for implanting a prototype suprachoroidal retinal prosthesis. The array implantation procedure was developed in 14 enucleated eyes. A full-thickness scleral incision was made parallel to the intermuscular septum and superotemporal to the lateral rectus muscle. A pocket was created in the suprachoroidal space, and the moulded electrode array was inserted. The scleral incision was closed and scleral anchor point sutured. In 9 of the 14 eyes examined, the device insertion was obstructed by the posterior ciliary neurovascular bundle. Subsequently, the position of this neurovascular bundle in 10 eyes was characterized. Implantation and lead routing procedure was then developed in six human cadavers. The array was tunnelled forward from behind the pinna to the orbit. Next, a lateral canthotomy was made. Lead fixation was established by creating an orbitotomy drilled in the frontal process of the zygomatic bone. The lateral rectus muscle was detached, and implantation was carried out. Finally, pinna to lateral canthus measurements were taken on 61 patients in order to determine optimal lead length., Results: These results identified potential anatomical obstructions and informed the anatomical fitting of the suprachoroidal retinal prosthesis., Conclusion: As a result of this work, a straightforward surgical approach for accurate anatomical suprachoroidal array and lead placement was developed for clinical application., (© 2013 The Authors. Clinical & Experimental Ophthalmology published by Wiley Publishing Asia Pty Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

Retinitis pigmentosa affects over 1.5 million people worldwide and is a leading cause of vision loss and blindness. While retinal prostheses have shown some success in restoring basic levels of vision, only generic, "one-size-fits-all" devices are currently being implanted. In this study, we used optical coherence tomography scans of the degenerated retina from 88 patients with retinitis pigmentosa to generate models of retinal thickness and curvature for the design of customized implants. We found the average retinal thickness at the fovea to be 152.9 ± 61.3 μm, increasing to a maximum retinal thickness of 250.9 ± 57.5 μm at a nasal eccentricity of 5°. These measures could be used to assist the development of custom-made penetrating electrodes to enhance and optimize epiretinal prostheses. From the retinal thickness measurements, we determined that the optimal length of penetrating electrodes to selectively stimulate retinal ganglion cell bodies and interneuron axons in the ganglion cell layer should be 30-100 μm, and to preferentially stimulate interneurons in the inner nuclear layer, electrodes should be 100-200 μm long. Electrodes greater than 200 μm long had the potential to penetrate through the retina into the choroid, which could cause devastating complications to the eye and should be avoided. The two- and three-dimensional models of retinal thickness developed in this study can be used to design patient-specific epiretinal implants that will help with safety and to optimize the efficacy of neuronal stimulation, ensuring the best functional performance of the device for patients., (Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Aim: The aims of this study were to (1) determine whether an instrumented measure will reduce measurement error to less than 5° in children with cerebral palsy (CP), (2) determine agreement and reliability of this instrumented measure in both conscious and anaesthetized participants, and (3) compare the method with previously reported measures., Method: Thirty-four ambulant children (15 males, 19 females), aged 3 to 9 years, with spastic CP were studied in a tertiary-care paediatric hospital (21 with hemiplegia, 11 with diplegia, and two with quadriplegia). The majority of children functioned at Gross Motor Function Classification System level I (n=11) or II (n=18), with five children at level III. Ankle dorsiflexion at 50% bodyweight was photographed and measured. Each child was measured when conscious and when under mask anaesthesia by two experienced assessors., Results: The standard error of measurement (SEM) ranged from 3.9° (anaesthetized; 95% confidence interval [CI] 3.3-4.0°) to 6.7° (conscious; 95% CI 5.3-8.0°). This compared favourably with previously reported dorsiflexion measures (SEM range 6.5-7.8°) in conscious children with CP. Intrarater reliability was good in both conditions (intraclass correlation coefficient [ICC]: range 0.95 [anaesthetized; 95% CI 0.92-0.98] to 0.86 [conscious; 95% CI 0.76-0.95]). The ICC for interrater reliability ranged from 0.87 (anaesthetized; 95% CI 0.81-0.93) to 0.65 (conscious; 95% CI 0.50-0.81)., Interpretation: Passive ankle dorsiflexion using an instrumented measure has face validity and may assist in the improvement of reproducibility under anaesthesia for clinical research. When an individual is conscious, this technique is not better than trained assessors using conventional goniometry reported in the literature and is not recommended for routine clinical use., (© 2013 Mac Keith Press.)

To significantly increase the resolution achievable by a retinal prosthesis without requiring additional electrodes, a current steering technique could be utilized. In this study, a finite element model was constructed to analyze the local concentrations of charge carrying ions within a saline bath due to concurrent stimulation from two electrodes surrounded by a hexagonal arrangement of return electrodes. By altering the return pathways, tissue activation and identification of unique stimulation patterns is possible. Ag/Ag-Cl electrodes and a voltage controlled current source were developed to validate the finite element model, with the model accurately predicting saline bath measurements. The average error in the returned currents between the finite element model and experimental results was 2% relative to the stimulus current.

Purpose: In order to develop retinal implants with a large number of electrodes, it is necessary to ensure that they do not cause damage to the neural tissue by the heat that the electrical circuits generate. Knowledge about the threshold of the amount of power that induces damage will assist in developing power budgets for retinal implants., Methods: Heat-induced retinal damage was evaluated by measuring changes in the morphology of the resident immune cells, the microglia, which are the first cells to respond to retinal trauma. Microglial soma and arbor areas were assessed in rat retinal tissues in vitro to determine the effects of increasing temperatures, implant contact, and heating and implant contact combined., Results: In response to increasing incubation temperatures (no implant), microglial somas enlarged and arbor areas retracted, indicative of retinal stress. Thermal damage thresholds, defined as a significant change in microglial morphology from that observed at the upper limit of normal body temperature, occurred at a temperature of 38.7 °C. Implant contact, induced when a passive implant was placed on the retina, also caused similar morphological alterations in microglia, indicating retinal damage. Heated-implant contact exacerbated the effects of temperature alone but still resulted in a thermal damage threshold of 38.7 °C, the same as with heating alone., Conclusions: Our conservative recommendations are that implanted retinal electronics keep power dissipations to less than 19 mW/mm(2) to stay below the microglial thermal damage threshold (2.1 °C) and to comply with international standards for implantable devices (2 °C).

In order to develop retinal implants with a large number of electrodes, it is necessary to ensure that they do not cause damage to the neural tissue by the heat that the electrical circuits generate. Knowledge of the amount of power that induces thermal damage will assist in development of power budgets for implants, which has a significant effect upon the design of the prostheses circuitry. In this study, temperatures were measured at multiple locations on the retina while the retina was heated in cadaver and in vivo preparations using a variety of prosthesis implantation sites. A finite element thermal model of the cat eye was also created and validated by the cadaver and in vivo tests, allowing for a much larger spectrum of thermal influences to be evaluated without additional animal experimentation. To ensure that retinal tissue temperatures are not increased by more than 2 °C, a 5 mm × 5 mm, suprachoroidally implanted heating element must not dissipate more than 135 mW (5.4 mW/mm (2))., (© 2011 IEEE)

In order to develop retinal implants with a large number of electrodes, it is necessary to ensure that they do not cause damage to the neural tissue by the heat that the electrical circuits generate. Knowledge about the threshold of the amount of power that induces thermal damage will greatly assist in development of power budgets for implants, which has a significant effect upon the design of implant circuitry. In this study, we developed and tested in-vitro equipment that can dissipate thermal energy in current prosthesis implantation sites while simultaneously measuring and recording temperature distributions at multiple locations along the retinal tissue. A finite element thermal model of the feline eye was also created and validated by the in-vitro tests allowing for a much larger spectrum of thermal influences to be evaluated without the additional cost of animal sacrifice.