Gil S. Rind

T-Type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures

Two high-affinity T-type calcium channel blockers attenuate neural activity in the thalamus and suppress seizures in a genetic model of absence epilepsy. To Soothe a Seizure Some epileptic children and adolescents experience “absence” seizures hundreds of times a day. Although apparently mild, these seizures—so named because they involve a sudden, brief absence of consciousness—can be dangerous if they occur during swimming or driving, for example. Unfortunately, the drugs available for treating such seizures are not completely effective. Tringham et al. sought to address this problem by rational drug design. Although the root cause of such seizures is not known, they are associated with abnormal, highly synchronous neuronal activity in certain brain regions. Voltage-gated ion channels, which have crucial functions in generating and propagating neuronal signals, likely play a key role. Several lines of evidence link one type of ion channel, low voltage–activated T-type calcium channels, to absence seizures. Using the structure of an N-type calcium channel blocker as a starting point, the researchers designed and screened small, focused libraries of compounds in a high-throughput assay that monitored calcium influx via a recombinant T-type channel. Two high-affinity T-type calcium channel blockers, termed Z941 and Z944, were identified; Z944 was highly selective for T-type channels and exhibited a preference for inactivated channels (the likely configuration in hyperexcited neurons). In a rat model of absence epilepsy, both compounds markedly reduced the time spent in seizures and the number of seizures per hour. In contrast to current first-line drugs for treating absence seizures, Z941 and Z944 also reduced the average seizure duration and cycle frequency. Both compounds were well tolerated in rats. Given its in vitro and in vivo activities, Z944 will progress to phase 1 clinical studies to test its safety in humans. Further studies will be needed to determine whether its marked effects in the rat model of absence epilepsy translate to the more complicated human condition. Absence seizures are a common seizure type in children with genetic generalized epilepsy and are characterized by a temporary loss of awareness, arrest of physical activity, and accompanying spike-and-wave discharges on an electroencephalogram. They arise from abnormal, hypersynchronous neuronal firing in brain thalamocortical circuits. Currently available therapeutic agents are only partially effective and act on multiple molecular targets, including γ-aminobutyric acid (GABA) transaminase, sodium channels, and calcium (Ca2+) channels. We sought to develop high-affinity T-type specific Ca2+ channel antagonists and to assess their efficacy against absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Using a rational drug design strategy that used knowledge from a previous N-type Ca2+ channel pharmacophore and a high-throughput fluorometric Ca2+ influx assay, we identified the T-type Ca2+ channel blockers Z941 and Z944 as candidate agents and showed in thalamic slices that they attenuated burst firing of thalamic reticular nucleus neurons in GAERS. Upon administration to GAERS animals, Z941 and Z944 potently suppressed absence seizures by 85 to 90% via a mechanism distinct from the effects of ethosuximide and valproate, two first-line clinical drugs for absence seizures. The ability of the T-type Ca2+ channel antagonists to inhibit absence seizures and to reduce the duration and cycle frequency of spike-and-wave discharges suggests that these agents have a unique mechanism of action on pathological thalamocortical oscillatory activity distinct from current drugs used in clinical practice.

Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity

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.

Suitability of nitinol electrodes in neural prostheses such as endovascular neural interfaces

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.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.

An ovine model of cerebral catheter venography for implantation of an endovascular neural interface

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.

Development and Implementation of a Corriedale Ovine Brain Atlas for Use in Atlas-Based Segmentation

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.

Signal quality of simultaneously recorded endovascular, subdural and epidural signals are comparable

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.

A Minimally Invasive Endovascular Stent-Electrode Array for Chronic Recordings of Cortical Neural Activity

Intracranial electrode arrays for recording and stimulating electrical brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. When compared to scalp electroencephalography (EEG), cortical recordings have demonstrated superior spatial resolution and consequently a greater potential for cognitive command output. Traditional cortical arrays require direct implantation into the brain via open craniotomy, which is a delicate and lengthy procedure. This can lead to inflammatory tissue responses amongst other clinical complications and has necessitated the development of minimally invasive methods that circumvent or mitigate brain trauma. In this study, we demonstrate the feasibility of chronically recording brain activity from within an external cerebral vein using a passive stent - electrode recording array (stentrode). We achieved implantation into a superficial cortical vein lying adjacent to the motor cortex using catheter angiography. Access was made via vascular puncture in the external jugular vein in the neck. Following successful implantation, we demonstrated neural recordings in freely moving sheep for time periods up to 190 days. Venous internal lumen patency was preserved for the duration of implantation. Spectral content and bandwidth of vascular electrocorticography were found to be comparable to those of recordings from epidural surface arrays.

The ovine motor cortex: A review of functional mapping and cytoarchitecture

HIGHLIGHTSSheep display complex behaviors such as facial recognition, emotion, and memory.Sheep motor cortex is responsible for goal‐directed effector independent tasks.Sheep brain has similar structure and grouping to other higher‐order mammals.Sheep have less clearly defined somatotopy than humans. ABSTRACT 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.